bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021‒04‒11
sixty-three papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. BCL3 couples cancer stem cell enrichment with pancreatic cancer molecular subtypes.
  2. Important role of Nfkb2 in the KrasG12D-driven carcinogenesis in the pancreas.
  3. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
  4. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis.
  5. Cell-programmed nutrient partitioning in the tumour microenvironment.
  6. FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition.
  7. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy.
  8. Structural variant evolution after telomere crisis.
  9. Age-associated expression of p21and p53 during human wound healing.
  10. Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes.
  11. The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis.
  12. Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
  13. Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription.
  14. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.
  15. Mechanistic origins of diverse genome rearrangements in cancer.
  16. Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival.
  17. Long-term yield of pancreatic cancer surveillance in high-risk individuals.
  18. TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.
  19. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia.
  20. Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
  21. Mitochondrial NADP+ is essential for proline biosynthesis during cell growth.
  22. Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism.
  23. RTN4B interacting protein FAM134C promotes ER membrane curvature and has a functional role in autophagy.
  24. Insulin action in adipocytes, adipose remodeling, and systemic effects.
  25. Single-cell RNA-seq reveals dynamic change in tumor microenvironment during pancreatic ductal adenocarcinoma malignant progression.
  26. Mechanisms of Resistance to KRASG12C-Targeted Therapy.
  27. Creatine promotes cancer metastasis through activation of Smad2/3.
  28. Glucose restriction drives spatial reorganization of mevalonate metabolism.
  29. Muscle Loss is Associated with Overall Survival in Patients with Metastatic Colorectal Cancer Independent of Tumor Mutational Status and Weight Loss.
  30. Artistoo, a library to build, share, and explore simulations of cells and tissues in the web browser.
  31. Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.
  32. Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
  33. Myeloid cell-derived HOCl is a paracrine effector that trans-inhibits IKK/NF-κB in melanoma cells and limits early tumor progression.
  34. DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics.
  35. Trends in the utilization of neoadjuvant therapy for pancreatic ductal adenocarcinoma.
  36. Organelle homeostasis principles: How organelle quality control and inter-organelle crosstalk promote cell survival.
  37. A resource of targeted mutant mouse lines for 5,061 genes.
  38. Treatment landscape of metastatic pancreatic cancer.
  39. History of preoperative therapy for pancreatic cancer and the MD Anderson experience.
  40. The hypothalamus for whole-body physiology: from metabolism to aging.
  41. Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial.
  42. QSER1 protects DNA methylation valleys from de novo methylation.
  43. Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.
  44. SHP2-mediated inhibition of DNA repair contributes to cGAS-STING activation and chemotherapeutic sensitivity in colon cancer.
  45. Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia.
  46. Prediction of biological age and evaluation of genome-wide dynamic methylomic changes throughout human aging.
  47. Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival.
  48. A rare germline CDKN2A variant (47T>G; p16-L16R) predisposes carriers to pancreatic cancer by reducing cell cycle inhibition.
  49. Pancreas cancer: Therapeutic trials in metastatic disease.
  50. Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress.
  51. siGCD: a web server to explore survival interaction of genes, cells and drugs in human cancers.
  52. Contemporary trials evaluating neoadjuvant therapy for resectable pancreatic cancer.
  53. Self-organized cell migration across scales - from single cell movement to tissue formation.
  54. Applicability of spatial transcriptional profiling to cancer research.
  55. Systemic immunity in cancer.
  56. Impact of adverse events of adjuvant and neoadjuvant chemotherapies on outcomes of patients with pancreatic ductal adenocarcinoma.
  57. Mitochondria and Its Permeability Transition Pore in Cancer Metabolic Reprogramming.
  58. Mechanosurveillance of tumour metastasis.
  59. Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer.
  60. The Role of Raman Spectroscopy Within Quantitative Metabolomics.
  61. RNA-Seq Data Analysis in Galaxy.
  62. Acute-on-Chronic Pancreatitis: Analysis of Clinical Profile and Outcome.
  63. Toward a multidisciplinary science of aging biology.
  1. Gastroenterology. 2021 Apr 02. pii: S0016-5085(21)00578-3. [Epub ahead of print]
    BCL3 couples cancer stem cell enrichment with pancreatic cancer molecular subtypes.
    Jiaoyu Ai, Sonja M Wörmann, Kıvanç Görgülü, Mireia Vallespinos, Sladjana Zagorac, Sonia Alcala, Nan Wu, Derya Kabacaoglu, Alexandra Berninger, Diego Navarro, Ezgi Kaya-Aksoy, Dietrich A Ruess, Katrin J Ciecielski, Marlena Kowalska, Ekin I Demir, Güralp O Ceyhan, Irina Heid, Rickmer Braren, Marc Riemann, Sabrina Schreiner, Samuel Hofmann, Maria Kutschke, Martin Jastroch, Julia Slotta-Huspenina, Alexander Muckenhuber, Anna Melissa Schlitter, Roland M Schmid, Katja Steiger, Kalliope N Diakopoulos, Marina Lesina, Bruno Sainz, Hana Algül.
      BACKGROUNG & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical NF-κB signaling member, as differing in pancreatic CSCs. To determine the biological consequences of Bcl3 silencing in vivo and in vitro, we generated Bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models and two independent patient cohorts. We assessed the correlation of BCL3 expression pattern with clinical parameters and subtypes.
    RESULTS: BCL3 was significantly downregulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via Bcl3 genetic knockout enhanced tumor burden, metastasis, EMT, and reduced overall survival. FACS analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays all indicated that Bcl3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.
    CONCLUSIONS: We demonstrate that Bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker predicting subtype characterization in PDAC thereby, allowing for personalized therapeutic approaches.
    Keywords:  BCL3; PDAC subtypes; cancer stem cell expansion; metastasis; pancreatic cancer
    DOI:  https://doi.org/10.1053/j.gastro.2021.03.051
  2. Pancreatology. 2021 Mar 26. pii: S1424-3903(21)00106-X. [Epub ahead of print]
    Important role of Nfkb2 in the KrasG12D-driven carcinogenesis in the pancreas.
    Zonera Hassan, Christian Schneeweis, Matthias Wirth, Sebastian Müller, Claudia Geismann, Thorsten Neuß, Katja Steiger, Oliver H Krämer, Roland M Schmid, Roland Rad, Alexander Arlt, Maximilian Reichert, Dieter Saur, Günter Schneider.
      BACKGROUND: Oncogenic Kras initiates and drives carcinogenesis in the pancreas by complex signaling networks, including activation of the NFκB pathway. Although recent evidence has shown that oncogenic gains in Nfκb2 collaborate with Kras in the carcinogenesis, no data at the level of genetics for the contribution of Nfκb2 is available so far.METHODS: We used Nfkb2 knock-out mice to decipher the role of the gene in Kras-driven carcinogenesis in vivo.
    RESULTS: We show that the Nfkb2 gene is needed for cancer initiation and progression in KrasG12D-driven models and this requirement of Nfkb2 is mechanistically connected to proliferative pathways. In contrast, Nfκb2 is dispensable in aggressive pancreatic ductal adenocarcinoma (PDAC) models relying on the simultaneous expression of the Kras oncogene and the mutated tumor suppressor p53.
    CONCLUSIONS: Our data add to the understanding of context-dependent requirements of oncogenic Kras signaling during pancreatic carcinogenesis.
    Keywords:  Kras; NFκB2; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.pan.2021.03.012
  3. Cell. 2021 Apr 02. pii: S0092-8674(21)00294-4. [Epub ahead of print]
    Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
    Stefan C Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven E Schumacher, Yu Fan, Matthew Fittall, Ruben M Drews, Xiaotong Yao, Thomas B K Watkins, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J Adams, Nicholas McGranahan, Charles Swanton, Gad Getz, Paul C Boutros, Marcin Imielinski, Rameen Beroukhim, S Cenk Sahinalp, Yuan Ji, Martin Peifer, Inigo Martincorena, Florian Markowetz, Ville Mustonen, Ke Yuan, Moritz Gerstung, Paul T Spellman, Wenyi Wang, Quaid D Morris, David C Wedge, Peter Van Loo, .
      Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
    Keywords:  branching evolution; cancer driver genes; cancer evolution; intra-tumor heterogeneity; pan-cancer genomics; subclonal reconstruction; tumor phylogeny; whole-genome sequencing
    DOI:  https://doi.org/10.1016/j.cell.2021.03.009
  4. Cell Metab. 2021 Mar 31. pii: S1550-4131(21)00115-7. [Epub ahead of print]
    Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis.
    Christopher D Wiley, Rishi Sharma, Sonnet S Davis, Jose Alberto Lopez-Dominguez, Kylie P Mitchell, Samantha Wiley, Fatouma Alimirah, Dong Eun Kim, Therese Payne, Andrew Rosko, Eliezer Aimontche, Sharvari M Deshpande, Francesco Neri, Chisaka Kuehnemann, Marco Demaria, Arvind Ramanathan, Judith Campisi.
      Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.
    Keywords:  15d-PGJ2; RAS; SASP; aging; biomarker; cellular senescence; dihomo-prostaglandin; eicosanoid; lipids; mass spectrometry; metabolomics; oxylipin; prostaglandin; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.008
  5. Nature. 2021 Apr 07.
    Cell-programmed nutrient partitioning in the tumour microenvironment.
    Bradley I Reinfeld, Matthew Z Madden, Melissa M Wolf, Anna Chytil, Jackie E Bader, Andrew R Patterson, Ayaka Sugiura, Allison S Cohen, Ahmed Ali, Brian T Do, Alexander Muir, Caroline A Lewis, Rachel A Hongo, Kirsten L Young, Rachel E Brown, Vera M Todd, Tessa Huffstater, Abin Abraham, Richard T O'Neil, Matthew H Wilson, Fuxue Xin, M Noor Tantawy, W David Merryman, Rachelle W Johnson, Christopher S Williams, Emily F Mason, Frank M Mason, Katherine E Beckermann, Matthew G Vander Heiden, H Charles Manning, Jeffrey C Rathmell, W Kimryn Rathmell.
      Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
    DOI:  https://doi.org/10.1038/s41586-021-03442-1
  6. J Clin Invest. 2021 Apr 06. pii: 145546. [Epub ahead of print]
    FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition.
    Shannon M Reilly, Mohammad Abu-Odeh, Magdalene Ameka, Julia H DeLuca, Meghan C Naber, Benyamin Dadpey, Nima Ebadat, Andrew V Gomez, Xiaoling Peng, BreAnne Poirier, Elyse Walk, Matthew J Potthoff, Alan R Saltiel.
      The protein kinases IKK-epsilon and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKK-epsilon/TBK1 inhibitor, amlexanox, produces weight loss and relieves insulin resistance in obese animals and patients. While amlexanox treatment caused a transient reduction in food intake, long-term weight loss was attributable to increased energy expenditure via FGF21-dependent beiging of WAT. Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, while hepatic secretion determined circulating levels, it was dispensable for regulating energy expenditure. In contrast, adipocyte-secreted FGF21 may have acted as an autocrine factor that leads to adipose tissue browning and weight loss in obese mice. Moreover, increased energy expenditure was an important determinant of improved insulin sensitivity by amlexanox. Conversely, the immediate reductions in fasting blood glucose observed with acute amlexanox treatment were mediated by suppression of hepatic glucose production via the activation of STAT3 by adipocyte-secreted IL-6. These findings demonstrate that amlexanox improved metabolic health via FGF21 action in adipocytes to increase energy expenditure via WAT beiging, and an endocrine role of adipocyte-derived IL-6 to decrease gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.
    Keywords:  Adipose tissue; Diabetes; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI145546
  7. Sci Adv. 2021 Apr;pii: eabg4544. [Epub ahead of print]7(15):
    AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy.
    Chien-Min Hung, Portia S Lombardo, Nazma Malik, Sonja N Brun, Kristina Hellberg, Jeanine L Van Nostrand, Daniel Garcia, Joshua Baumgart, Ken Diffenderfer, John M Asara, Reuben J Shaw.
      The serine/threonine kinase ULK1 mediates autophagy initiation in response to various cellular stresses, and genetic deletion of ULK1 leads to accumulation of damaged mitochondria. Here we identify Parkin, the core ubiquitin ligase in mitophagy, and PARK2 gene product mutated in familial Parkinson's disease, as a ULK1 substrate. Recent studies uncovered a nine residue ("ACT") domain important for Parkin activation, and we demonstrate that AMPK-dependent ULK1 rapidly phosphorylates conserved serine108 in the ACT domain in response to mitochondrial stress. Phosphorylation of Parkin Ser108 occurs maximally within five minutes of mitochondrial damage, unlike activation of PINK1 and TBK1, which is observed thirty to sixty minutes later. Mutation of the ULK1 phosphorylation sites in Parkin, genetic AMPK or ULK1 depletion, or pharmacologic ULK1 inhibition, all lead to delays in Parkin activation and defects in assays of Parkin function and downstream mitophagy events. These findings reveal an unexpected first step in the mitophagy cascade.
    DOI:  https://doi.org/10.1126/sciadv.abg4544
  8. Nat Commun. 2021 04 07. 12(1): 2093
    Structural variant evolution after telomere crisis.
    Sally M Dewhurst, Xiaotong Yao, Joel Rosiene, Huasong Tian, Julie Behr, Nazario Bosco, Kaori K Takai, Titia de Lange, Marcin Imieliński.
      Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.
    DOI:  https://doi.org/10.1038/s41467-021-21933-7
  9. Aging Cell. 2021 Apr 09. e13354
    Age-associated expression of p21and p53 during human wound healing.
    Chee W Chia, Cheryl A Sherman-Baust, Sara A Larson, Ritu Pandey, Roxanne Withers, Ajoy C Karikkineth, Linda M Zukley, Judith Campisi, Josephine M Egan, Ranjan Sen, Luigi Ferrucci.
      In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.
    Keywords:  aging; human wound healing; p21; p53
    DOI:  https://doi.org/10.1111/acel.13354
  10. Cancer Discov. 2021 Apr 05.
    Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes.
    Marco Avolio, Livio Trusolino.
      Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1531
  11. EMBO Rep. 2021 Apr 06. e51532
    The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis.
    Toshitaka Nakamura, Motoyuki Ogawa, Kazuki Kojima, Saki Takayanagi, Shunya Ishihara, Kazuki Hattori, Isao Naguro, Hidenori Ichijo.
      Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemia-reperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.
    Keywords:  CRISPR screening; Ca2+; MICU1; cold stress-induced ferroptosis; mitochondria
    DOI:  https://doi.org/10.15252/embr.202051532
  12. Mol Cell. 2021 Apr 04. pii: S1097-2765(21)00214-8. [Epub ahead of print]
    Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
    Alice Clare Newman, Mattia Falcone, Alejandro Huerta Uribe, Tong Zhang, Dimitris Athineos, Matthias Pietzke, Alexei Vazquez, Karen Blyth, Oliver David Kenneth Maddocks.
      Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.
    Keywords:  IDO1; IFNγ; PDAC; cancer immunology; cancer metabolism; epacadostat; formate; immunometabolism; immunotherapy; one-carbon metabolism; pancreas; serine; stellate cells; tryptophan; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.019
  13. Cancer Cell. 2021 Mar 30. pii: S1535-6108(21)00164-1. [Epub ahead of print]
    Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription.
    Yanfen Zhu, Amit D Gujar, Chee-Hong Wong, Harianto Tjong, Chew Yee Ngan, Liang Gong, Yi-An Chen, Hoon Kim, Jihe Liu, Meihong Li, Adam Mil-Homens, Rahul Maurya, Chris Kuhlberg, Fanyue Sun, Eunhee Yi, Ana C deCarvalho, Yijun Ruan, Roel G W Verhaak, Chia-Lin Wei.
      Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterized oncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatin interaction assays to characterize genome-wide ecDNA-mediated chromatin contacts that impact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derived neurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNA and genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterized by broad and high-level H3K27ac signals converging predominantly on chromosomal genes of increased expression levels. Prostate cancer cells harboring synthetic ecDNA circles composed of characterized enhancers result in the genome-wide activation of chromosomal gene transcription. Deciphering the chromosomal targets of ecDNAs at single-molecule resolution reveals an association with actively expressed oncogenes spatially clustered within ecDNA-directed interaction networks. Our results suggest that ecDNA can function as mobile transcriptional enhancers to promote tumor progression and manifest a potential synthetic aneuploidy mechanism of transcription control in cancer.
    Keywords:  ChIA-Drop; ChIA-PET; chromatin interactions; ecDNA; mobile enhancers
    DOI:  https://doi.org/10.1016/j.ccell.2021.03.006
  14. Nat Metab. 2021 Apr 08.
    Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.
    Alexander N Gorelick, Minsoo Kim, Walid K Chatila, Konnor La, A Ari Hakimi, Michael F Berger, Barry S Taylor, Payam A Gammage, Ed Reznik.
      Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development.
    DOI:  https://doi.org/10.1038/s42255-021-00378-8
  15. Semin Cell Dev Biol. 2021 Apr 03. pii: S1084-9521(21)00035-5. [Epub ahead of print]
    Mechanistic origins of diverse genome rearrangements in cancer.
    Rashmi Dahiya, Qing Hu, Peter Ly.
      Cancer genomes frequently harbor structural chromosomal rearrangements that disrupt the linear DNA sequence order and copy number. To date, diverse classes of structural variants have been identified across multiple cancer types. These aberrations span a wide spectrum of complexity, ranging from simple translocations to intricate patterns of rearrangements involving multiple chromosomes. Although most somatic rearrangements are acquired gradually throughout tumorigenesis, recent interrogation of cancer genomes have uncovered novel categories of complex rearrangements that arises rapidly through a one-off catastrophic event, including chromothripsis and chromoplexy. Here we review the cellular and molecular mechanisms contributing to the formation of diverse structural rearrangement classes during cancer development. Genotoxic stress from a myriad of extrinsic and intrinsic sources can trigger DNA double-strand breaks that are subjected to DNA repair with potentially mutagenic outcomes. We also highlight how aberrant nuclear structures generated through mitotic cell division errors, such as rupture-prone micronuclei and chromosome bridges, can instigate massive DNA damage and the formation of complex rearrangements in cancer genomes.
    Keywords:  Cancer genomes; Chromosome rearrangements; Chromothripsis; DNA damage; DNA repair; Genomic instability; Micronuclei; Mitosis
    DOI:  https://doi.org/10.1016/j.semcdb.2021.03.003
  16. Sci Rep. 2021 Apr 07. 11(1): 7570
    Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival.
    Manuel Gentiluomo, Chiara Corradi, Giuseppe Vanella, Astrid Z Johansen, Oliver Strobel, Andrea Szentesi, Anna Caterina Milanetto, Péter Hegyi, Juozas Kupcinskas, Francesca Tavano, John P Neoptolemos, Dania Bozzato, Thilo Hackert, Raffaele Pezzilli, Julia S Johansen, Eithne Costello, Beatrice Mohelnikova-Duchonova, Casper H J van Eijck, Renata Talar-Wojnarowska, Carsten Palnæs Hansen, Erika Darvasi, Inna M Chen, Giulia Martina Cavestro, Pavel Soucek, Liliana Piredda, Pavel Vodicka, Maria Gazouli, Paolo Giorgio Arcidiacono, Federico Canzian, Daniele Campa, Gabriele Capurso.
      Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.
    DOI:  https://doi.org/10.1038/s41598-021-87130-0
  17. Gut. 2021 Apr 05. pii: gutjnl-2020-323611. [Epub ahead of print]
    Long-term yield of pancreatic cancer surveillance in high-risk individuals.
    Kasper A Overbeek, Iris J M Levink, Brechtje D M Koopmann, Femme Harinck, Ingrid C A W Konings, Margreet G E M Ausems, Anja Wagner, Paul Fockens, Casper H van Eijck, Bas Groot Koerkamp, Olivier R C Busch, Marc G Besselink, Barbara A J Bastiaansen, Lydi M J W van Driel, Nicole S Erler, Frank P Vleggaar, Jan-Werner Poley, Djuna L Cahen, Jeanin E van Hooft, Marco J Bruno, .
      OBJECTIVE: We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DESIGN: From 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.
    RESULTS: 366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).
    CONCLUSION: The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.
    Keywords:  endoscopic ultrasonography; family cancer; magnetic resonance imaging; pancreatic cancer; surveillance
    DOI:  https://doi.org/10.1136/gutjnl-2020-323611
  18. Cell Mol Life Sci. 2021 Apr 08.
    TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.
    Jianling Xie, Stuart P De Poi, Sean J Humphrey, Leanne K Hein, John B Bruning, Wenru Pan, Luke A Selth, Timothy J Sargeant, Christopher G Proud.
      The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1 that might act as driver oncogenes by causing hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, tuberous sclerosis complex. We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth, proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving an increased rate of anaerobic glycolysis, while Rheb-E40K regulates the translation factor eEF2 and autophagy, likely through differential interactions with 5' AMP-activated protein kinase (AMPK) which modulate its activity. Our findings suggest that unique, personalized, combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.
    Keywords:  AMPK; PKM; Rheb; TSC; eEF2; mTOR
    DOI:  https://doi.org/10.1007/s00018-021-03825-7
  19. Cell Metab. 2021 Apr 06. pii: S1550-4131(21)00127-3. [Epub ahead of print]33(4): 758-780
    The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia.
    Lykke Sylow, Victoria L Tokarz, Erik A Richter, Amira Klip.
      As the principal tissue for insulin-stimulated glucose disposal, skeletal muscle is a primary driver of whole-body glycemic control. Skeletal muscle also uniquely responds to muscle contraction or exercise with increased sensitivity to subsequent insulin stimulation. Insulin's dominating control of glucose metabolism is orchestrated by complex and highly regulated signaling cascades that elicit diverse and unique effects on skeletal muscle. We discuss the discoveries that have led to our current understanding of how insulin promotes glucose uptake in muscle. We also touch upon insulin access to muscle, and insulin signaling toward glycogen, lipid, and protein metabolism. We draw from human and rodent studies in vivo, isolated muscle preparations, and muscle cell cultures to home in on the molecular, biophysical, and structural elements mediating these responses. Finally, we offer some perspective on molecular defects that potentially underlie the failure of muscle to take up glucose efficiently during obesity and type 2 diabetes.
    Keywords:  GLUT4; diabetes; exercise-induced sensitization to insulin; glucose uptake; glycogen; insulin; insulin resistance; insulin signaling; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.020
  20. Cancer Gene Ther. 2021 Apr 08.
    Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
    Tatsunori Suzuki, Takahiro Kishikawa, Tatsuyuki Sato, Norihiko Takeda, Yuki Sugiura, Takahiro Seimiya, Kazuma Sekiba, Motoko Ohno, Takuma Iwata, Rei Ishibashi, Motoyuki Otsuka, Kazuhiko Koike.
      Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
    DOI:  https://doi.org/10.1038/s41417-021-00326-4
  21. Nat Metab. 2021 Apr 08.
    Mitochondrial NADP+ is essential for proline biosynthesis during cell growth.
    Diem H Tran, Rushendhiran Kesavan, Halie Rion, Mona Hoseini Soflaee, Ashley Solmonson, Divya Bezwada, Hieu S Vu, Feng Cai, John A Phillips, Ralph J DeBerardinis, Gerta Hoxhaj.
      Nicotinamide adenine dinucleotide phosphate (NADP+) is vital to produce NADPH, a principal supplier of reducing power for biosynthesis of macromolecules and protection against oxidative stress. NADPH exists in separate pools, in both the cytosol and mitochondria; however, the cellular functions of mitochondrial NADPH are incompletely described. Here, we find that decreasing mitochondrial NADP(H) levels through depletion of NAD kinase 2 (NADK2), an enzyme responsible for production of mitochondrial NADP+, renders cells uniquely proline auxotrophic. Cells with NADK2 deletion fail to synthesize proline, due to mitochondrial NADPH deficiency. We uncover the requirement of mitochondrial NADPH and NADK2 activity for the generation of the pyrroline-5-carboxylate metabolite intermediate as the bottleneck step in the proline biosynthesis pathway. Notably, after NADK2 deletion, proline is required to support nucleotide and protein synthesis, making proline essential for the growth and proliferation of NADK2-deficient cells. Thus, we highlight proline auxotrophy in mammalian cells and discover that mitochondrial NADPH is essential to enable proline biosynthesis.
    DOI:  https://doi.org/10.1038/s42255-021-00374-y
  22. J Clin Invest. 2021 Apr 06. pii: 134073. [Epub ahead of print]
    Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism.
    Emily R Watts, Andrew Jm Howden, Tyler Morrison, Pranvera Sadiku, Jens L Hukelmann, Alex von Kriegsheim, Bart Ghesquière, Fiona Murphy, Ananda S Mirchandani, Duncan C Humphries, Robert Grecian, Eilise M Ryan, Patricia Coelho, Giovanny Rodriguez-Blanco, Tracie M Plant, Rebecca S Dickinson, Andrew J Finch, Wesley Vermaelen, Doreen A Cantrell, Moira Kb Whyte, Sarah R Walmsley.
      Limiting dysfunctional neutrophilic inflammation whilst preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labelled amino acids into metabolic enzymes, pro-inflammatory mediators and granule proteins we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycaemia, characteristic of inflamed tissues, promoted this extra-cellular protein scavenging with activation of the lysosomal compartment further driving exploitation of the protein rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways which enable neutrophils to sustain synthetic and effector functions in the tissues.
    Keywords:  Hypoxia; Inflammation; Metabolism; Neutrophils; Proteomics
    DOI:  https://doi.org/10.1172/JCI134073
  23. Mol Biol Cell. 2021 Apr 07. mbcE20060409
    RTN4B interacting protein FAM134C promotes ER membrane curvature and has a functional role in autophagy.
    Darshan Kumar, Behnam Lak, Taina Suntio, Helena Vihinen, Ilya Belevich, Tiina Viita, Liu Xiaonan, Aki Vartiainen, Maria Vartiainen, Markku Varjosalo, Eija Jokitalo.
      The endoplasmic reticulum (ER) is comprised of a controlled ratio of sheets and tubules, which are maintained by several proteins with multiple functions. Reticulons (RTNs), especially RTN4, and DP1/Yop1p family members are known to induce ER membrane curvature. RTN4B is the main RTN4 isoform expressed in non-neuronal cells. In this study, we identified FAM134C as a RTN4B interacting protein in mammalian, non-neuronal cells. FAM134C localized specifically to the ER tubules and sheet edges. Ultrastructural analysis revealed that overexpression of FAM134C induced formation of unbranched, long tubules or dense globular structures comprised of heavily branched narrow tubules. In both cases, tubules were non-motile. ER tubulation was dependent on the reticulon homology domain (RHD) close to the N-terminus. FAM134C plays a role in the autophagy pathway as its level elevated significantly upon amino acid starvation but not during ER stress. Moreover, FAM134C depletion reduced the number and size of autophagic structures and the amount of ER as a cargo within autophagic structures under starvation conditions. Dominant-negative expression of FAM134C forms with mutated RHD or LC3 interacting region (LIR) also led to the reduced number of autophagic structures. Our results suggest that FAM134C provides a link between regulation of ER architecture and ER turnover by promoting ER tubulation required for subsequent ER fragmentation and engulfment into autophagosomes. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E20-06-0409
  24. Cell Metab. 2021 Apr 06. pii: S1550-4131(21)00126-1. [Epub ahead of print]33(4): 748-757
    Insulin action in adipocytes, adipose remodeling, and systemic effects.
    Anna Santoro, Timothy E McGraw, Barbara B Kahn.
      On this 100th anniversary of the discovery of insulin, we recognize the critical role that adipocytes, which are exquisitely responsive to insulin, have played in determining the mechanisms for insulin action at the cellular level. Our understanding of adipose tissue biology has evolved greatly, and it is now clear that adipocytes are far more complicated than simple storage depots for fat. A growing body of evidence documents how adipocytes, in response to insulin, contribute to the control of whole-body nutrient homeostasis. These advances highlight adipocyte plasticity, heterogeneity, and endocrine function, unique features that connect adipocyte metabolism to the regulation of other tissues important for metabolic homeostasis (e.g., liver, muscle, pancreas).
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.019
  25. EBioMedicine. 2021 Apr 02. pii: S2352-3964(21)00108-0. [Epub ahead of print]66 103315
    Single-cell RNA-seq reveals dynamic change in tumor microenvironment during pancreatic ductal adenocarcinoma malignant progression.
    Kai Chen, Qi Wang, Mingzhe Li, Huahu Guo, Weikang Liu, Feng Wang, Xiaodong Tian, Yinmo Yang.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is most aggressive among all gastrointestinal tumors. The complex intra-tumor heterogeneity and special tumor microenvironment in PDAC bring great challenges for developing effective treatment strategies. We aimed to delineate dynamic changes of tumor microenvironment components during PDAC malignant progression utilizing single-cell RNA sequencing.METHODS: A total of 11 samples (4 PDAC I, 4 PDAC II, 3 PDAC III) were used to construct expression matrix. After identifying distinct cell clusters, subcluster analysis for each cluster was performed. New cancer associated fibroblasts (CAFs) subset was validated by weighted gene co-expression network analysis, RNA in situ hybridization and immunofluorescence.
    FINDINGS: We found that ductal cells were not dominant component while tumor infiltrating immune cells and pancreatic stellate cells gradually accumulated during tumor development. We defined several new Treg and exhausted T cell signature genes, including DUSP4, FANK1 and LAIR2. The analysis of TCGA datasets showed that patients with high expression of DUSP4 had significantly worse prognosis. In addition, we identified a new CAFs subset (complement-secreting CAFs, csCAFs), which specifically expresses complement system components, and constructed csCAFs-related module by weighted gene co-expression network analysis. The csCAFs were located in the tissue stroma adjacent to malignant ductal cells only in early PDAC.
    INTERPRETATION: We systematically explored PDAC heterogeneity and identified csCAFs as a new CAFs subset special to PDAC, which may be valuable for understanding the crosstalk inside tumor.
    FUNDING: This study was supported by The Natural Science Foundation of China (NO.81572339, 81672353, 81871954) and the Youth Clinical Research Project of Peking University First Hospital (2018CR28).
    Keywords:  Cancer associated fibroblasts; Intra-tumor heterogeneity; Pancreatic cancer; Tumor microenvironment; scRNA-seq
    DOI:  https://doi.org/10.1016/j.ebiom.2021.103315
  26. Cancer Discov. 2021 Apr 05.
    Mechanisms of Resistance to KRASG12C-Targeted Therapy.
    Neal S Akhave, Amadeo B Biter, David S Hong.
      KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research. SIGNIFICANCE: Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1616
  27. Cell Metab. 2021 Mar 27. pii: S1550-4131(21)00116-9. [Epub ahead of print]
    Creatine promotes cancer metastasis through activation of Smad2/3.
    Liwen Zhang, Zijing Zhu, Huiwen Yan, Wen Wang, Zhenzhen Wu, Fei Zhang, Qixiang Zhang, Guizhi Shi, Junfeng Du, Huiyun Cai, Xuanxuan Zhang, David Hsu, Pu Gao, Hai-Long Piao, Gang Chen, Pengcheng Bu.
      As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.
    Keywords:  GATM; MPS1; SLC6A8; Smad2; Smad3; breast cancer; colorectal cancer; creatine; metastasis
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.009
  28. Elife. 2021 Apr 07. pii: e62591. [Epub ahead of print]10
    Glucose restriction drives spatial reorganization of mevalonate metabolism.
    Sean M Rogers, Hanaa Hariri, N Ezgi M Wood, Natalie Ortiz Speer, W Mike Henne.
      Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high molecular weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.62591
  29. Oncologist. 2021 Apr 05.
    Muscle Loss is Associated with Overall Survival in Patients with Metastatic Colorectal Cancer Independent of Tumor Mutational Status and Weight Loss.
    T D Best Cand, E J Roeland, N K Horick, E E Van Seventer, A El-Jawahri, A S Troschel Cand, P C Johnson, K N Kanter, M G Fish, J P Marquardt Cand, C P Bridge, J S Temel, R B Corcoran, R D Nipp, F J Fintelmann.
      BACKGROUND: Survival in patients with metastatic colorectal cancer (mCRC) has been associated with tumor mutational status, muscle loss, and weight loss. We sought to explore the combined effects of these variables on overall survival.MATERIALS AND METHODS: We performed an observational cohort study, prospectively enrolling patients receiving chemotherapy for mCRC. We retrospectively assessed changes in muscle (using computed tomography) and weight, each dichotomized as >5% or ≤5% loss, at 3-, 6-, and 12-months after diagnosis of mCRC. We used regression models to assess relationships between tumor mutational status, muscle loss, weight loss, and overall survival. Additionally, we evaluated associations between muscle loss, weight loss, and tumor mutational status.
    RESULTS: We included 226 patients (mean age 59±13, 53% male). Tumor mutational status included 44% wild type, 42% RAS-mutant, and 14% BRAF-mutant. Patients with >5% muscle loss at 3- and 12-months experienced worse survival controlling for mutational status and weight (3-months hazard ratio 2.66; P<.001; 12-months hazard ratio 2.10; P=.031). We found an association of >5% muscle loss with BRAF-mutational status at 6- and 12-months. Weight loss was not associated with survival nor mutational status.
    CONCLUSION: Increased muscle loss at 3- and 12-months may identify patients with mCRC at risk for decreased overall survival, independent of tumor mutational status. Specifically, >5% muscle loss identifies patients within each category of tumor mutational status with decreased overall survival in our sample. Our findings suggest that quantifying muscle loss on serial computed tomography scans may refine survival estimates in patients with mCRC.
    IMPLICATIONS FOR PRACTICE: In this study of 226 patients with metastatic colorectal cancer, we found that losing >5% skeletal muscle at 3- and 12-months after the diagnosis of metastatic disease was associated with worse overall survival, independent of tumor mutational status and weight loss. Interestingly, we did not find a significant association between weight loss and overall survival. Our findings suggest that muscle quantification on serial computed tomography may refine survival estimates in patients with metastatic colorectal cancer beyond mutational status.
    Keywords:  body composition; colorectal cancer; outcomes; sarcopenia; skeletal muscle; survival
    DOI:  https://doi.org/10.1002/onco.13774
  30. Elife. 2021 Apr 09. pii: e61288. [Epub ahead of print]10
    Artistoo, a library to build, share, and explore simulations of cells and tissues in the web browser.
    Inge M N Wortel, Johannes Textor.
      The Cellular Potts Model (CPM) is a powerful in silico method for simulating biological processes at tissue scale. Their inherently graphical nature makes CPMs very accessible in theory, but in practice, they are mostly implemented in specialised frameworks users need to master before they can run simulations. We here present Artistoo (Artificial Tissue Toolbox), a JavaScript library for building 'explorable' CPM simulations where viewers can change parameters interactively, exploring their effects in real time. Simulations run directly in the web browser and do not require third-party software, plugins, or back-end servers. The JavaScript implementation imposes no major performance loss compared to frameworks written in C++; Artistoo remains sufficiently fast for interactive, real time simulations. Artistoo provides an opportunity to unlock CPM models for a broader audience: Interactive simulations can be shared via a URL in a zero-install setting. We discuss applications in CPM research, science dissemination, open science, and education.
    Keywords:  cell biology; computational biology; none; systems biology
    DOI:  https://doi.org/10.7554/eLife.61288
  31. Gut. 2021 Apr 07. pii: gutjnl-2020-323014. [Epub ahead of print]
    Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.
    Zhibo Xie, Ya Gao, Chiakang Ho, Lequn Li, Chen Jin, Xiaoyi Wang, Caifeng Zou, Yishen Mao, Xiaobo Wang, Qingfeng Li, Deliang Fu, Yi-Fan Zhang.
      OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis.DESIGN: C57BL/6 mice were 'educated' by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models.
    RESULTS: Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis.
    CONCLUSION: The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.
    Keywords:  extracellular matrix; fibrosis; liver metastases; molecular oncology; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2020-323014
  32. Clin Cancer Res. 2021 Apr 09.
    Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
    Li Wang, John P Sfakianos, Kristin G Beaumont, Guray Akturk, Amir Horowitz, Robert P Sebra, Adam M Farkas, Sacha Gnjatic, Austin Hake, Sudeh Izadmehr, Peter Wiklund, William K Oh, Peter M Szabo, Megan Wind-Rotolo, Keziban Unsal-Kacmaz, Xin Yao, Eric Schadt, Padmanee Sharma, Nina Bhardwaj, Jun Zhu, Matthew D Galsky.
      PURPOSE: To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer.EXPERIMENTAL DESIGN: We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
    RESULTS: We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer.
    CONCLUSIONS: The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4574
  33. Sci Signal. 2021 Apr 06. pii: eaax5971. [Epub ahead of print]14(677):
    Myeloid cell-derived HOCl is a paracrine effector that trans-inhibits IKK/NF-κB in melanoma cells and limits early tumor progression.
    Tracy W Liu, Seth T Gammon, Ping Yang, David Fuentes, David Piwnica-Worms.
      The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity. Upon MDC activation, MPO is secreted into phagosomes where it catalyzes the production of hypochlorous acid (HOCl), a potent chlorinating oxidant. Here, we demonstrated that the myeloid lineage-restricted MPO-HOCl system had antitumor effects in early melanoma growth in aged mice. Orthotopic melanomas grew more slowly in immunocompetent MPO+/+ host mice compared to age-matched syngeneic MPO-/- mice. Real-time intravital tumor imaging in vivo and in cell cocultures revealed a cell-cell proximity-dependent association between MDC-derived MPO enzyme activity and blockade of ligand-induced IκBα degradation in tumor cells. HOCl directly trans-inhibited IκB kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor κB (NF-κB) transcriptional activation and inducing changes in the expression of genes involved in metabolic pathways, cell cycle progression, and DNA replication. By contrast, HOCl induced transcriptional changes in CD8+ T cells related to ion transport and the MAPK and PI3K-AKT signaling pathways that are associated with T cell activation. MPO increased the circulating concentrations of the myeloid cell-attracting cytokines CXCL1 and CXCL5, enhanced local infiltration by CD8+ cytotoxic T cells, and decreased tumor growth. Overall, these data reveal a role for MDC-derived HOCl as a small-molecule paracrine signaling factor that trans-inhibits IKK in melanoma tumor cells, mediating antitumor responses during early tumor progression.
    DOI:  https://doi.org/10.1126/scisignal.aax5971
  34. Proc Natl Acad Sci U S A. 2021 Mar 16. pii: e2021073118. [Epub ahead of print]118(11):
    DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics.
    Yoon Jeong Park, Sangseon Lee, Sangsoo Lim, Hahn Nahmgoong, Yul Ji, Jin Young Huh, Assim A Alfadda, Sun Kim, Jae Bum Kim.
      White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.
    Keywords:  DNA methylation; adiposity; chromosome structure; metabolic disease; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2021073118
  35. J Surg Oncol. 2021 May;123(6): 1432-1440
    Trends in the utilization of neoadjuvant therapy for pancreatic ductal adenocarcinoma.
    Zachary J Brown, Jordan M Cloyd.
      For patients with localized pancreatic cancer, neoadjuvant therapy (NT) is increasingly delivered before surgery to maximize the receipt of multimodality therapy and the odds of a margin-negative resection. Three decades of refining the use of NT have led to its acceptance as a valid treatment approach for pancreatic adenocarcinoma. In this review, we discuss the rationale for and recent global trends in the utilization of NT for patients with pancreatic cancer.
    Keywords:  FOLFIRINOX; neoadjuvant chemotherapy; pancreatic cancer; pancreatoduodenectomy; preoperative therapy; whipple
    DOI:  https://doi.org/10.1002/jso.26384
  36. Dev Cell. 2021 Apr 05. pii: S1534-5807(21)00209-4. [Epub ahead of print]56(7): 878-880
    Organelle homeostasis principles: How organelle quality control and inter-organelle crosstalk promote cell survival.
    W Mike Henne.
      To survive, cells sense their surroundings and adapt to enable homeostasis. Studies dissecting this process reveal organizational principles, including quality-control pathways, changes to organelle shape, and inter-organelle communication, that facilitate metabolic or developmental remodeling. In this issue, several reviews discuss these organelle homeostasis principles and how they are altered in disease.
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.012
  37. Nat Genet. 2021 Apr;53(4): 416-419
    A resource of targeted mutant mouse lines for 5,061 genes.
    Marie-Christine Birling, Atsushi Yoshiki, David J Adams, Shinya Ayabe, Arthur L Beaudet, Joanna Bottomley, Allan Bradley, Steve D M Brown, Antje Bürger, Wendy Bushell, Francesco Chiani, Hsian-Jean Genie Chin, Skevoulla Christou, Gemma F Codner, Francesco J DeMayo, Mary E Dickinson, Brendan Doe, Leah Rae Donahue, Martin D Fray, Alessia Gambadoro, Xiang Gao, Marina Gertsenstein, Alba Gomez-Segura, Leslie O Goodwin, Jason D Heaney, Yann Hérault, Martin Hrabe de Angelis, Si-Tse Jiang, Monica J Justice, Petr Kasparek, Ruairidh E King, Ralf Kühn, Ho Lee, Young Jae Lee, Zhiwei Liu, K C Kent Lloyd, Isabel Lorenzo, Ann-Marie Mallon, Colin McKerlie, Terrence F Meehan, Violeta Munoz Fuentes, Stuart Newman, Lauryl M J Nutter, Goo Taeg Oh, Guillaume Pavlovic, Ramiro Ramirez-Solis, Barry Rosen, Edward J Ryder, Luis A Santos, Joel Schick, John R Seavitt, Radislav Sedlacek, Claudia Seisenberger, Je Kyung Seong, William C Skarnes, Tania Sorg, Karen P Steel, Masaru Tamura, Glauco P Tocchini-Valentini, Chi-Kuang Leo Wang, Hannah Wardle-Jones, Marie Wattenhofer-Donzé, Sara Wells, Michael V Wiles, Brandon J Willis, Joshua A Wood, Wolfgang Wurst, Ying Xu, , Lydia Teboul, Stephen A Murray.
      
    DOI:  https://doi.org/10.1038/s41588-021-00825-y
  38. Cancer Treat Rev. 2021 Mar 17. pii: S0305-7372(21)00028-1. [Epub ahead of print]96 102180
    Treatment landscape of metastatic pancreatic cancer.
    Sara De Dosso, Alexander R Siebenhüner, Thomas Winder, Alexander Meisel, Ralph Fritsch, Christoforos Astaras, Petr Szturz, Markus Borner.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.
    Keywords:  Biomarkers; FOLFIRINOX; Gemcitabine; Liposomal-irinotecan; Nab-paclitaxel; Pancreatic cancer; Precision medicine
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102180
  39. J Surg Oncol. 2021 May;123(6): 1414-1422
    History of preoperative therapy for pancreatic cancer and the MD Anderson experience.
    Cameron E Gaskill, Jessica Maxwell, Naruhiko Ikoma, Michael P Kim, Ching-Wei Tzeng, Jeffrey E Lee, Matthew H G Katz.
      Systemic chemotherapy improves the survival of patients who undergo pancreatectomy, but whether chemotherapy should be delivered before or after surgery remains debated. At The University of Texas MD Anderson Cancer Center, localized pancreatic ductal adenocarcinoma (PDAC) has been preferentially treated with preoperative therapy-a practice supported by a robust history of institutional and national trials. In the following review, we discuss the historical use of perioperative therapy, our experience with it at MD Anderson Cancer Center and internationally, and the future of treatment and trials for PDAC.
    Keywords:  chemoradiation; chemotherapy; neoadjuvant; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1002/jso.26394
  40. Protein Cell. 2021 Apr 07.
    The hypothalamus for whole-body physiology: from metabolism to aging.
    Tiemin Liu, Yong Xu, Chun-Xia Yi, Qingchun Tong, Dongsheng Cai.
      Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.
    Keywords:  aging; hypothalamus; metabolism; neuron; obesity
    DOI:  https://doi.org/10.1007/s13238-021-00834-x
  41. Eur J Cancer. 2021 Mar 31. pii: S0959-8049(21)00106-4. [Epub ahead of print]148 422-429
    Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial.
    Stefano Cascinu, Rossana Berardi, Roberto Bianco, Domenico Bilancia, Alberto Zaniboni, Daris Ferrari, Stefania Mosconi, Andrea Spallanzani, Luigi Cavanna, Silvana Leo, Francesca Negri, Giordano D Beretta, Alberto Sobrero, Maria Banzi, Alberto Morabito, Alessandro Bittoni, Roberta Marciano, Domenica Ferrara, Silvia Noventa, Maria C Piccirillo, Roberto Labianca, Cristina Mosconi, Andrea Casadei Gardini, Ciro Gallo, Francesco Perrone.
      BACKGROUND: The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials.METHODS: This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points.
    FINDINGS: A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke.
    INTERPRETATION: NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. CLINICALTRIALS.
    GOV IDENTIFIER: NCT02043730.
    Keywords:  Advanced pancreatic cancer; Paclitaxel and gemcitabine; Phase II randomized trial
    DOI:  https://doi.org/10.1016/j.ejca.2021.02.023
  42. Science. 2021 Apr 09. pii: eabd0875. [Epub ahead of print]372(6538):
    QSER1 protects DNA methylation valleys from de novo methylation.
    Gary Dixon, Heng Pan, Dapeng Yang, Bess P Rosen, Therande Jashari, Nipun Verma, Julian Pulecio, Inbal Caspi, Kihyun Lee, Stephanie Stransky, Abigail Glezer, Chang Liu, Marco Rivas, Ritu Kumar, Yahui Lan, Ingrid Torregroza, Chuan He, Simone Sidoli, Todd Evans, Olivier Elemento, Danwei Huangfu.
      DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.
    DOI:  https://doi.org/10.1126/science.abd0875
  43. Cancer Cell Int. 2021 Apr 07. 21(1): 196
    Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.
    Rong Tang, Xiaomeng Liu, Wei Wang, Jie Hua, Jin Xu, Chen Liang, Qingcai Meng, Jiang Liu, Bo Zhang, Xianjun Yu, Si Shi.
      BACKGROUND: High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.METHODS: The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study.
    RESULTS: The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.
    CONCLUSION: This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.
    Keywords:  Immune microenvironment; Microsatellite instability; Molecular oncology; Pancreatic cancer; Tumor mutation burden
    DOI:  https://doi.org/10.1186/s12935-021-01900-4
  44. Cancer Res. 2021 Apr 05. pii: canres.3738.2020. [Epub ahead of print]
    SHP2-mediated inhibition of DNA repair contributes to cGAS-STING activation and chemotherapeutic sensitivity in colon cancer.
    Bin Wei, Lingyan Xu, Wenjie Guo, Yuanyuan Wang, Jingjing Wu, Xiaofei Li, Xiaomin Cai, Jinbo Hu, Meijing Wang, Qiang Xu, Wen Liu, Yanhong Gu.
      As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an important role in anti-tumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated poly ADP-ribose polymerase (PARP1) after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated anti-tumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3738
  45. Nat Commun. 2021 04 06. 12(1): 2057
    Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia.
    Brennan Olson, Xinxia Zhu, Mason A Norgard, Peter R Levasseur, John T Butler, Abigail Buenafe, Kevin G Burfeind, Katherine A Michaelis, Katherine R Pelz, Heike Mendez, Jared Edwards, Stephanie M Krasnow, Aaron J Grossberg, Daniel L Marks.
      Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2's proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.
    DOI:  https://doi.org/10.1038/s41467-021-22361-3
  46. G3 (Bethesda). 2021 Apr 07. pii: jkab112. [Epub ahead of print]
    Prediction of biological age and evaluation of genome-wide dynamic methylomic changes throughout human aging.
    Mahmoud Amiri Roudbar, Seyedeh Fatemeh Mousavi, Siavash Salek Ardestani, Fernando Brito Lopes, Mehdi Momen, Daniel Gianola, Hasan Khatib.
      The use of DNA methylation signatures to predict chronological age and aging rate is of interest in many fields, including disease prevention and treatment, forensics, and anti-aging medicine. Although a large number of methylation markers are significantly associated with age, most age-prediction methods use a few markers selected based on either previously published studies or datasets containing methylation information. Here, we implemented reproducing kernel Hilbert spaces (RKHS) regression and a ridge regression model in a Bayesian framework that utilized phenotypic and methylation profiles simultaneously to predict chronological age. We used over 450,000 CpG sites from the whole blood of a large cohort of 4,409 human individuals with a range of 10-101 years of age. Models were fitted using adjusted and un-adjusted methylation measurements for cell heterogeneity. Un-adjusted methylation scores delivered a significantly higher prediction accuracy than adjusted methylation data, with a correlation between age and predicted age of 0.98 and a root-mean-square error (RMSE) of 3.54 years in un-adjusted data, and 0.90 (correlation) and 7.16 (RMSE) years in adjusted data. Reducing the number of predictors (CpG sites) through subset selection improved predictive power with a correlation of 0.98 and an RMSE of 2.98 years in the RKHS model. We found distinct global methylation patterns, with a significant increase in the proportion of methylated cytosines in CpG islands and a decreased proportion in other CpG types, including CpG shore, shelf, and open sea (p < 5e-06). Epigenetic drift seemed to be a widespread phenomenon as more than 97% of the age-associated methylation sites had heteroscedasticity. Apparent methylomic aging rate (AMAR) had a sex-specific pattern, with an increase in AMAR in females with age related to males.
    Keywords:  Aging; Bayesian ridge regression; Reproducing kernel Hilbert spaces; Whole-methylome prediction
    DOI:  https://doi.org/10.1093/g3journal/jkab112
  47. Pancreatology. 2021 Apr 01. pii: S1424-3903(21)00134-4. [Epub ahead of print]
    Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival.
    Jun Zhao, Luisa M Solis Soto, Hua Wang, Matthew H Katz, Laura R Prakash, Michael Kim, Ching-Wei D Tzeng, Jeffrey E Lee, Robert A Wolff, Yanqing Huang, Ignacio I Wistuba, Anirban Maitra, Huamin Wang.
      BACKGROUND: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear.METHODS: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4+, CD8+, CD21+ and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs.
    RESULTS: CD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4+ TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort.
    CONCLUSIONS: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4+, CD8+ and CD21+ TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.
    Keywords:  Adenosine; CD73; Immunotherapy; Pancreatic cancer; Prognosis; Tumor infiltrating lymphocytes; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.pan.2021.03.018
  48. J Biol Chem. 2021 Apr 03. pii: S0021-9258(21)00420-8. [Epub ahead of print] 100634
    A rare germline CDKN2A variant (47T>G; p16-L16R) predisposes carriers to pancreatic cancer by reducing cell cycle inhibition.
    Isaac P Horn, David L Marks, Amanda N Koenig, Tara L Hogenson, Luciana L Almada, Lauren E Goldstein, Paola A Romecin Duran, Renzo Vera, Anne M Vrabel, Gaofeng Cui, Kari G Rabe, William R Bamlet, Georges Mer, Hugues Sicotte, Cheng Zhang, Hu Li, Gloria M Petersen, Martin E Fernandez-Zapico.
      Germline mutations in CDKN2A, encoding the tumor suppressor p16, are responsible for a large proportion of familial melanoma cases, and also increase risk of pancreatic cancer. We identified four families through pancreatic cancer probands that were affected by both cancers. These families bore a germline missense variant of CDKN2A (47T>G), encoding a p16-L16R mutant protein associated with high cancer occurrence. Here, we investigated the biological significance of this variant. When transfected into p16-null pancreatic cancer cells, p16-L16R was expressed at lower levels than wild type (WT) p16. In addition, p16-L16R was unable to bind CDK4 or CDK6 compared to WT p16, as shown by coimmunoprecipitation assays ,and also was impaired in its ability to inhibit the cell cycle, as demonstrated by flow cytometry analyses. In silico molecular modeling predicted that the L16R mutation prevents normal protein folding, consistent with the observed reduction in expression/stability and diminished function of this mutant protein. We isolated normal dermal fibroblasts from members of the families expressing WT or L16R proteins to investigate the impact of endogenous p16-L16R mutant protein on cell growth. In culture, p16-L16R fibroblasts grew at a faster rate, and most survived until later passages than p16-WT fibroblasts. Further, Western blotting demonstrated that p16 protein was detected at lower levels in p16-L16R than in p16-WT fibroblasts. Together, these results suggest that the presence of a are CDKN2A (47T>G) mutant allele contributes to an increased risk of pancreatic cancer as a result of reduced p16 protein levels and diminished p16 tumor suppressor function.
    Keywords:  CDK4; cancer biology; cell cycle; cell proliferation; fibroblast; genetic disease; inherited mutation; melanoma; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1016/j.jbc.2021.100634
  49. J Surg Oncol. 2021 May;123(6): 1475-1488
    Pancreas cancer: Therapeutic trials in metastatic disease.
    James W Smithy, Eileen M O'Reilly.
      Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality in 2021. Cytotoxic therapies are the therapeutic mainstay for PDAC. The recent approval of olaparib as maintenance therapy for germline BRCA1/2-mutated PDAC and pembrolizumab for mismatch repair deficient PDAC represent molecularly targeted approaches for this disease. Investigational therapeutic strategies include targeting the stroma, metabolism, tumor microenvironment, and the immune system, and selected approaches are reviewed herein.
    Keywords:  KRAS; clinical trials; genetics; metastatic disease; pancreatic cancer
    DOI:  https://doi.org/10.1002/jso.26359
  50. JCI Insight. 2021 Apr 08. pii: 137876. [Epub ahead of print]6(7):
    Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress.
    Iwao Shimomura, Naoaki Watanabe, Tomofumi Yamamoto, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto.
      Lung cancer with oncogenic KRAS makes up a significant proportion of lung cancers and is accompanied by a poor prognosis. Recent advances in understanding the molecular pathogenesis of lung cancer with oncogenic KRAS have enabled the development of drugs, yet mutated KRAS remains undruggable. We performed small-molecule library screening and identified verteporfin, a yes-associated protein 1 (YAP1) inhibitor; verteporfin treatment markedly reduced cell viability in KRAS-mutant lung cancer cells in vitro and suppressed KRAS-driven lung tumorigenesis in vivo. Comparative functional analysis of verteporfin treatment and YAP1 knockdown with siRNA revealed that the cytotoxic effect of verteporfin was at least partially independent of YAP1 inhibition. A whole-transcriptome approach revealed the distinct expression profiles in KRAS-mutant lung cancer cells between verteporfin treatment and YAP1 knockdown and identified the selective involvement of the ER stress pathway in the effects of verteporfin treatment in KRAS-mutant lung cancer, leading to apoptotic cell death. These data provide novel insight to uncover vulnerabilities in KRAS-driven lung tumorigenesis.
    Keywords:  Cell Biology; Drug screens; Lung cancer; Oncogenes; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.137876
  51. Brief Bioinform. 2021 Apr 05. pii: bbab058. [Epub ahead of print]
    siGCD: a web server to explore survival interaction of genes, cells and drugs in human cancers.
    XiuLiang Cui, Lu Han, Yang Liu, Ying Li, Wen Sun, Bin Song, Wenxia Zhou, Yongxiang Zhang, Hongyang Wang.
      It is pivotal and remains challenge for cancer precision treatment to identify the survival outcome interactions between genes, cells and drugs. Here, we present siGCD, a web-based tool for analysis and visualization of the survival interaction of Genes, Cells and Drugs in human cancers. siGCD utilizes the cancer heterogeneity to simulate the manipulated gene expression, cell infiltration and drug treatment, which overcomes the data and experimental limitations. To illustrate the performance of siGCD, we identified the survival interaction partners of EGFR (gene level), T cells (cell level) and sorafenib (drug level), and our prediction was consistent with previous reports. Moreover, we validate the synergistic effect of regorafenib and glyburide, and found that glyburide could significantly improve the regorafenib response. These results demonstrate that siGCD could benefit cancer precision medicine in a wide range of advantageous application scenarios including gene regulatory network construction, immune cell regulatory gene identification, drug (especially multiple target drugs) response biomarker screening and combination therapeutic design.
    Keywords:  biomarker; drug combination; immune cell; survival interaction
    DOI:  https://doi.org/10.1093/bib/bbab058
  52. J Surg Oncol. 2021 May;123(6): 1423-1431
    Contemporary trials evaluating neoadjuvant therapy for resectable pancreatic cancer.
    Akhil Chawla.
      While the use of neoadjuvant therapy is well-accepted in the treatment of borderline resectable and locally advanced pancreatic cancers, the benefit of neoadjuvant chemotherapy in patients with resectable disease has been a topic of debate. Recently, key trials evaluating neoadjuvant chemotherapy for resectable pancreatic cancer have reported results. This review describes key clinical trials evaluating the use of preoperative therapy in patients with technically resectable pancreatic cancer with a focus on their contribution to the available evidence.
    Keywords:  chemotherapy; neoadjuvant therapy; pancreatic cancer; resectable pancreatic cancer
    DOI:  https://doi.org/10.1002/jso.26393
  53. Development. 2021 Apr 06. pii: dev191767. [Epub ahead of print]148(7):
    Self-organized cell migration across scales - from single cell movement to tissue formation.
    Jessica Stock, Andrea Pauli.
      Self-organization is a key feature of many biological and developmental processes, including cell migration. Although cell migration has traditionally been viewed as a biological response to extrinsic signals, advances within the past two decades have highlighted the importance of intrinsic self-organizing properties to direct cell migration on multiple scales. In this Review, we will explore self-organizing mechanisms that lay the foundation for both single and collective cell migration. Based on in vitro and in vivo examples, we will discuss theoretical concepts that underlie the persistent migration of single cells in the absence of directional guidance cues, and the formation of an autonomous cell collective that drives coordinated migration. Finally, we highlight the general implications of self-organizing principles guiding cell migration for biological and medical research.
    Keywords:  Cell migration; Self-organization; Symmetry breaking
    DOI:  https://doi.org/10.1242/dev.191767
  54. Mol Cell. 2021 Mar 27. pii: S1097-2765(21)00211-2. [Epub ahead of print]
    Applicability of spatial transcriptional profiling to cancer research.
    Rania Bassiouni, Lee D Gibbs, David W Craig, John D Carpten, Troy A McEachron.
      Spatial transcriptional profiling provides gene expression information within the important anatomical context of tissue architecture. This approach is well suited to characterizing solid tumors, which develop within a complex landscape of malignant cells, immune cells, and stroma. In a single assay, spatial transcriptional profiling can interrogate the role of spatial relationships among these cell populations as well as reveal spatial patterns of relevant oncogenic genetic events. The broad utility of this approach is reflected in the array of strategies that have been developed for its implementation as well as in the recent commercial development of several profiling platforms. The flexibility to apply these technologies to both hypothesis-driven and discovery-driven studies allows widespread applicability in research settings. This review discusses available technologies for spatial transcriptional profiling and several applications for their use in cancer research.
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.016
  55. Nat Rev Cancer. 2021 Apr 09.
    Systemic immunity in cancer.
    Kamir J Hiam-Galvez, Breanna M Allen, Matthew H Spitzer.
      Immunotherapy has revolutionized cancer treatment, but efficacy remains limited in most clinical settings. Cancer is a systemic disease that induces many functional and compositional changes to the immune system as a whole. Immunity is regulated by interactions of diverse cell lineages across tissues. Therefore, an improved understanding of tumour immunology must assess the systemic immune landscape beyond the tumour microenvironment (TME). Importantly, the peripheral immune system is required to drive effective natural and therapeutically induced antitumour immune responses. In fact, emerging evidence suggests that immunotherapy drives new immune responses rather than the reinvigoration of pre-existing immune responses. However, new immune responses in individuals burdened with tumours are compromised even beyond the TME. Herein, we aim to comprehensively outline the current knowledge of systemic immunity in cancer.
    DOI:  https://doi.org/10.1038/s41568-021-00347-z
  56. Cancer Chemother Pharmacol. 2021 Apr 07.
    Impact of adverse events of adjuvant and neoadjuvant chemotherapies on outcomes of patients with pancreatic ductal adenocarcinoma.
    Shozo Mori, Taku Aoki, Yuhki Sakuraoka, Takayuki Shimizu, Takamune Yamaguchi, Kyung-Hwa Park, Takatsugu Matsumoto, Takayuki Shiraki, Yukihiro Iso, Keiichi Kubota.
      PURPOSE: Recently, the number of patients with pancreatic ductal adenocarcinoma (PDAC) who have received both neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) has been increasing. However, whether adverse events (AEs) during AC influence the prognosis of patients with resected PDAC who do or do not receive NAC remains uncertain.METHODS: Patients with PDAC who underwent a pancreatectomy between 2011 and 2019 were divided into two groups: an upfront surgery (UFS) group (n = 72), and an NAC group (n = 77). Patients who received AC were then divided into two groups: an AE grade 0/1/2 group (AE-G-0/1/2) and an AE grade 3/4 group (AE-G-3/4). The relationship between AEs and patient outcome and predictors of AE-G-3/4 were investigated.
    RESULTS: AC was used in 54 and 65 patients in the UFS and NAC groups, respectively. In the NAC group, the relative dose intensity (RDI) and AC completion rate as well as the overall survival rate of patients with AE-G-3/4 (n = 15) during AC were significantly worse than those of patients with AE-G-0/1/2 (n = 50). However, similar differences were not observed in the UFS group. A multivariate analysis revealed that AE-G-3/4 during NAC, AC agent (gemcitabine), an albumin level < 3.5 g/dL, and an estimated glomerular filtration rate < 90 mL/min/1.73 m2 before the initiation of AC were independent predictors of AE-G-3/4 during AC.
    CONCLUSIONS: AE-G-3/4 during AC was associated with a lower RDI and AC completion rate and a worse outcome among patients with PDAC who had received NAC.
    Keywords:  Adjuvant chemotherapy; Gemcitabine; Neoadjuvant chemotherapy; Pancreatic cancer; S-1
    DOI:  https://doi.org/10.1007/s00280-021-04267-5
  57. Biochem Pharmacol. 2021 Mar 31. pii: S0006-2952(21)00133-7. [Epub ahead of print] 114537
    Mitochondria and Its Permeability Transition Pore in Cancer Metabolic Reprogramming.
    Lishu Guo.
      Mitochondria are a major source of ATP provision as well as cellular suicidal weapon store. Accumulating evidences demonstrate that mitochondrial bioenergetics, biosynthesis and signaling are important mediators of tumorigenesis. Metabolic plasticity enables cancer cell reprogramming to cope with cellular and environmental alterations, a process requires mitochondria biology. Mitochondrial metabolism emerges to be a promising arena for cancer therapeutic targets. The permeability transition pore (PTP) participates in physiological Ca2+ and ROS homeostasis as well as cell death depending on the open state. The hypothesis that PTP forms from F-ATP synthase provide clues to the potential collaborative role of mitochondrial respiration and PTP in regulating cancer cell fate and metabolic reprogramming.
    Keywords:  Ca(2+); F-ATP synthase; PTP; ROS; cancer; metabolic reprogramming; mitochondria; permeability transition
    DOI:  https://doi.org/10.1016/j.bcp.2021.114537
  58. Nat Rev Immunol. 2021 Apr 07.
    Mechanosurveillance of tumour metastasis.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-021-00546-7
  59. Cell. 2021 Apr 01. pii: S0092-8674(21)00223-3. [Epub ahead of print]
    Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer.
    Michael Levin.
      How are individual cell behaviors coordinated toward invariant large-scale anatomical outcomes in development and regeneration despite unpredictable perturbations? Endogenous distributions of membrane potentials, produced by ion channels and gap junctions, are present across all tissues. These bioelectrical networks process morphogenetic information that controls gene expression, enabling cell collectives to make decisions about large-scale growth and form. Recent progress in the analysis and computational modeling of developmental bioelectric circuits and channelopathies reveals how cellular collectives cooperate toward organ-level structural order. These advances suggest a roadmap for exploiting bioelectric signaling for interventions addressing developmental disorders, regenerative medicine, cancer reprogramming, and synthetic bioengineering.
    Keywords:  bioelectricity; development; electroceuticals; gap junction; ion channel; morphogenesis
    DOI:  https://doi.org/10.1016/j.cell.2021.02.034
  60. Annu Rev Anal Chem (Palo Alto Calif). 2021 Apr 07.
    The Role of Raman Spectroscopy Within Quantitative Metabolomics.
    Cassio Lima, Howbeer Muhamadali, Royston Goodacre.
      Ninety-two years have passed since the discovery of the Raman effect, and there are currently more than 25 different types of Raman-based techniques. The past two decades have witnessed the blossoming of Raman spectroscopy as a powerful physicochemical technique with broad applications within the life sciences. In this review, we critique the use of Raman spectroscopy as a tool for quantitative metabolomics. We overview recent developments of Raman spectroscopy for identification and quantification of disease biomarkers in liquid biopsy, with a focus on the recent advances within surface-enhanced Raman scattering-based methods. Ultimately, we discuss the applications of imaging modalities based on Raman scattering as label-free methods to study the abundance and distribution of biomolecules in cells and tissues, including mammalian, algal, and bacterial cells. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 14 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-anchem-091420-092323
  61. Methods Mol Biol. 2021 ;2284 367-392
    RNA-Seq Data Analysis in Galaxy.
    Bérénice Batut, Marius van den Beek, Maria A Doyle, Nicola Soranzo.
      A complete RNA-Seq analysis involves the use of several different tools, with substantial software and computational requirements. The Galaxy platform simplifies the execution of such bioinformatics analyses by embedding the needed tools in its web interface, while also providing reproducibility. Here, we describe how to perform a reference-based RNA-Seq analysis using Galaxy, from data upload to visualization and functional enrichment analysis of differentially expressed genes.
    Keywords:  Differential gene expression; Functional enrichment; Galaxy; Quality control; Sequence mapping; Visualizations; Workflow
    DOI:  https://doi.org/10.1007/978-1-0716-1307-8_20
  62. Cureus. 2021 Apr 01. 13(4): e14242
    Acute-on-Chronic Pancreatitis: Analysis of Clinical Profile and Outcome.
    Dibyajyoti Sharma, Bipadabhanjan Mallick, Jayanta Samanta, Vikas Gupta, Saroj K Sinha, Rakesh Kochhar.
      OBJECTIVE: Overall, a handful of studies are available on the outcomes of acute-on-chronic pancreatitis (ACP). We aimed to provide a more complete and updated picture of ACP.METHODS: We evaluated consecutive patients of acute exacerbation of chronic pancreatitis (CP) in a tertiary care center located in north India and studied their epidemiological profiles, etiological factors as well as outcomes.
    RESULTS: Forty-five patients of ACP with a mean age of 37±13 years were evaluated. The majority of the patients were male (75%) and alcohol was the most common detectable etiology while no etiology could be identified in 35% of patients after extensive laboratory investigations and imaging. Moderately severe pancreatitis was noted in 73% of patients and 49% of patients had necrotizing pancreatitis out of which the majority (33%) had both pancreatic as well as extra-pancreatic necrosis (EPN). Five patients (11%) were subjected to percutaneous catheter drainage. Persistent organ failure was noted in 9% of patients and two (4.5%) patients had died from organ failure.
    CONCLUSION: To conclude, this study has demonstrated that ACP has a milder disease course and low morbidity and mortality. Early elimination of the etiological factor is essential for optimal outcome.
    Keywords:  acute-on-chronic pancreatitis; clinical profile; outcome
    DOI:  https://doi.org/10.7759/cureus.14242
  63. Mech Ageing Dev. 2021 Apr 02. pii: S0047-6374(21)00053-1. [Epub ahead of print] 111481
    Toward a multidisciplinary science of aging biology.
    Alan A Cohen, Tamàs Fülöp.
      
    DOI:  https://doi.org/10.1016/j.mad.2021.111481
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