bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒08‒14
33 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. A pulse-chasable reporter processing assay for mammalian autophagic flux with HaloTag.
  2. Lipid droplets promote efficient mitophagy.
  3. TMEM164 is a new determinant of autophagy-dependent ferroptosis.
  4. Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype.
  5. Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.
  6. Calcium, mitochondria and the initiation of acute pancreatitis.
  7. Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer.
  8. Functional and biological heterogeneity of KRASQ61 mutations.
  9. Systematic comparison of pancreatic ductal adenocarcinoma models identifies a conserved highly plastic basal cell state.
  10. Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition.
  11. Cellular senescence and senolytics: the path to the clinic.
  12. Chemotherapy treatment induces pro-invasive changes in liver ECM composition.
  13. CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer.
  14. Targeting Plk1 sensitizes pancreatic cancer to immune checkpoint therapy.
  15. MALDI-MSI: A Powerful Approach to Understand Primary Pancreatic Ductal Adenocarcinoma and Metastases.
  16. BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.
  17. Exploring cell and tissue mechanics with optical tweezers.
  18. Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance.
  19. Skin manifestations of pancreatic diseases.
  20. Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.
  21. Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis.
  22. Comprehensive comparison of the prognostic value of systemic inflammation biomarkers for cancer cachexia: a multicenter prospective study.
  23. The importance of biological sex in cardiac cachexia.
  24. Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
  25. Impact of metabolic stress induced by diets, aging and fasting on tissue oxygen consumption.
  26. Introducing the Lipidomics Minimal Reporting Checklist.
  27. Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes.
  28. Artificial intelligence for the detection of pancreatic lesions.
  29. Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology.
  30. Activating translation with phase separation.
  31. Analysis of germline-driven ancestry-associated gene expression in cancers.
  32. Cancer nanomedicine.
  33. Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
  1. Elife. 2022 Aug 08. pii: e78923. [Epub ahead of print]11
    A pulse-chasable reporter processing assay for mammalian autophagic flux with HaloTag.
    Willa Wen-You Yim, Hayashi Yamamoto, Noboru Mizushima.
      Monitoring autophagic flux is necessary for most autophagy studies. The autophagic flux assays currently available for mammalian cells are generally complicated and do not yield highly quantitative results. Yeast autophagic flux is routinely monitored with the GFP-based processing assay, whereby the amount of GFP proteolytically released from GFP-containing reporters (e.g., GFP-Atg8), detected by immunoblotting, reflects autophagic flux. However, this simple and effective assay is typically inapplicable to mammalian cells because GFP is efficiently degraded in lysosomes while the more proteolytically resistant RFP accumulates in lysosomes under basal conditions. Here, we report a HaloTag (Halo)-based reporter processing assay to monitor mammalian autophagic flux. We found that Halo is sensitive to lysosomal proteolysis but becomes resistant upon ligand binding. When delivered into lysosomes by autophagy, pulse-labeled Halo-based reporters (e.g., Halo-LC3 and Halo-GFP) are proteolytically processed to generate Haloligand when delivered into lysosomes by autophagy. Hence, the amount of free Haloligand detected by immunoblotting or in-gel fluorescence imaging reflects autophagic flux. We demonstrate the applications of this assay by monitoring the autophagy pathways, macroautophagy, selective autophagy, and even bulk nonselective autophagy. With the Halo-based processing assay, mammalian autophagic flux and lysosome-mediated degradation can be monitored easily and precisely.
    Keywords:  cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.78923
  2. Autophagy. 2022 Aug 08. 1-2
    Lipid droplets promote efficient mitophagy.
    Maeve Long, Thomas G McWilliams.
      Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.
    Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2089956
  3. Autophagy. 2022 Aug 10.
    TMEM164 is a new determinant of autophagy-dependent ferroptosis.
    Jiao Liu, Yang Liu, Yuan Wang, Changfeng Li, Yangchun Xie, Daniel J Klionsky, Rui Kang, Daolin Tang.
      Macroautophagy (hereafter "autophagy") is a membrane-mediated biological process that involves engulfing and delivering cytoplasmic components to lysosomes for degradation. In addition to autophagy's pro-survival effect during nutrient starvation, excessive activation of autophagy machinery can also cause regulated cell death, especially iron-dependent ferroptosis. Here, we report a key role for TMEM164 (transmembrane protein 164) in selectively mediating ATG5 (autophagy related 5)-dependent autophagosome formation during ferroptosis, rather than during starvation. In contrast, the membrane protein ATG9A (autophagy related 9A) is dispensable for the formation of autophagosomes during ferroptosis. TMEM164-mediated autophagy degrades ferritin, GPX4 (glutathione peroxidase 4), and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death. Consequently, the loss of TMEM164 limits the anticancer activity of ferroptosis-mediated cytotoxicity in mice. High TMEM164 expression is associated with improved survival and increased immune cell infiltration in patients with pancreatic cancer. These findings establish a new mode of autophagy-dependent ferroptosis.
    Keywords:  Autophagy; cell death; ferroptosis; membrane protein; tumor immunity
    DOI:  https://doi.org/10.1080/15548627.2022.2111635
  4. Gut. 2022 Aug 09. pii: gutjnl-2021-326550. [Epub ahead of print]
    Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype.
    Sven-Thorsten Liffers, Laura Godfrey, Lisa Frohn, Lena Haeberle, Aslihan Yavas, Rita Vesce, Wolfgang Goering, Friederike V Opitz, Nickolas Stoecklein, Wolfram Trudo Knoefel, Anna Melissa Schlitter, Guenter Klöppel, Elisa Espinet, Andreas Trumpp, Jens T Siveke, Irene Esposito.
      OBJECTIVE: Due to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions.DESIGN: Targeted and whole-genome low-coverage sequencing, genome-wide methylation and transcriptome analyses were applied on a final collective of 122 morphologically well-characterised low-grade and high-grade PDAC precursors, including intestinal and gastric intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasias (PanIN).
    RESULTS: Epigenetic regulation of mucin genes determines the phenotype of PDAC precursors. PanIN and gastric IPMN display a ductal molecular profile and numerous similarly regulated pathways, including the Notch pathway, but can be distinguished by recurrent deletions and differential methylation and, in part, by the expression of mucin-like 3. Intestinal IPMN are clearly distinct lesions at the molecular level with a more instable genotype and are possibly related to a different ductal cell compartment.
    CONCLUSIONS: PDAC precursors with gastric and intestinal phenotype are heterogeneous in terms of morphology, genetic and epigenetic profile. This heterogeneity is related to a different cell identity and, possibly, to a different aetiology.
    Keywords:  gene expression; gene mutation; pancreatic pathology; pancreatic tumours; pre-malignancy - GI tract
    DOI:  https://doi.org/10.1136/gutjnl-2021-326550
  5. Nat Commun. 2022 Aug 08. 13(1): 4633
    Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.
    Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R M Zunica, Roger J Liang, Jessica Murphy, Corey D Holman, Curtis J Bare, Gregory Ghahramani, Zhidan Wu, David E Cohen, John P Kirwan, Lewis C Cantley, Christopher L Axelrod, Marcus D Goncalves.
      Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.
    DOI:  https://doi.org/10.1038/s41467-022-32135-0
  6. Pancreatology. 2022 Aug 03. pii: S1424-3903(22)00466-5. [Epub ahead of print]
    Calcium, mitochondria and the initiation of acute pancreatitis.
    Stephen J Pandol, Roberta A Gottlieb.
      Acute pancreatitis is characterized by necrosis of its parenchymal cells and influx and activation of inflammatory cells that further promote injury and necrosis. This review is intended to discuss the central role of disorders of calcium metabolism and mitochondrial dysfunction in the mechanism of pancreatitis development. The disorders are placed in context of calcium and mitochondria in physiologic function of the pancreas. Moreover, we discuss potential therapeutics for preventing pathologic calcium signals that injure mitochondria and interventions that promote the removal of injured mitochondria and regenerate new and heathy populations of mitochondria.
    Keywords:  Acute pancreatitis; Autophagy; Calcium; Inflammation; Mitochondria; Mitophagy; Necrosis
    DOI:  https://doi.org/10.1016/j.pan.2022.07.011
  7. Gastroenterology. 2022 Aug 07. pii: S0016-5085(22)00905-2. [Epub ahead of print]
    Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer.
    Jashodeep Datta, Xizi Dai, Anna Bianchi, Iago De Castro Silva, Siddharth Mehra, Vanessa Garrido, Purushottam Lamichhane, Samara Singh, Zhiqun Zhou, Austin R Dosch, Fanuel Messaggio, Yuguang Ban, Oliver Umland, Peter J Hosein, Nagaraj S Nagathihalli, Nipun B Merchant.
      BACKGROUND: We have shown that reciprocally activated RAS/MEK and JAK/STAT3 pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine if MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC.METHODS: CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i(ruxolitinib)- vs. vehicle-treated Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). CRISPR/Cas9-silencing of CAF-restricted Map2k1/Mek1 and/or Stat3 enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via time-of-flight mass cytometry were examined in PKT mice treated with vehicle, anti-PD1 monotherapy, and MEKi+STAT3i combined with anti-PD1.
    RESULTS: MEKi+STAT3i attenuates Il6/Cxcl1-expressing pro-inflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of CD8+ T-cells which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, since CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration in-vivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves anti-tumor responses and survival in PKT mice, but also augments recruitment of activated/memory T-cells while improving their degranulating and cytotoxic capacity, compared with anti-PD-1 monotherapy. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) yielded clinical benefit.
    CONCLUSIONS: Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.
    Keywords:  Pancreatic ductal adenocarcinoma; immune checkpoint inhibition; immunotherapy; mesenchymal stem cell; stromal plasticity
    DOI:  https://doi.org/10.1053/j.gastro.2022.07.076
  8. Sci Signal. 2022 Aug 09. 15(746): eabn2694
    Functional and biological heterogeneity of KRASQ61 mutations.
    Minh V Huynh, G Aaron Hobbs, Antje Schaefer, Mariaelena Pierobon, Leiah M Carey, J Nathaniel Diehl, Jonathan M DeLiberty, Ryan D Thurman, Adelaide R Cooke, Craig M Goodwin, Joshua H Cook, Lin Lin, Andrew M Waters, Naim U Rashid, Emanuel F Petricoin, Sharon L Campbell, Kevin M Haigis, Diane M Simeone, Costas A Lyssiotis, Adrienne D Cox, Channing J Der.
      Missense mutations at the three hotspots in the guanosine triphosphatase (GTPase) RAS-Gly12, Gly13, and Gln61 (commonly known as G12, G13, and Q61, respectively)-occur differentially among the three RAS isoforms. Q61 mutations in KRAS are infrequent and differ markedly in occurrence. Q61H is the predominant mutant (at 57%), followed by Q61R/L/K (collectively 40%), and Q61P and Q61E are the rarest (2 and 1%, respectively). Probability analysis suggested that mutational susceptibility to different DNA base changes cannot account for this distribution. Therefore, we investigated whether these frequencies might be explained by differences in the biochemical, structural, and biological properties of KRASQ61 mutants. Expression of KRASQ61 mutants in NIH 3T3 fibroblasts and RIE-1 epithelial cells caused various alterations in morphology, growth transformation, effector signaling, and metabolism. The relatively rare KRASQ61E mutant stimulated actin stress fiber formation, a phenotype distinct from that of KRASQ61H/R/L/P, which disrupted actin cytoskeletal organization. The crystal structure of KRASQ61E was unexpectedly similar to that of wild-type KRAS, a potential basis for its weak oncogenicity. KRASQ61H/L/R-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines exhibited KRAS-dependent growth and, as observed with KRASG12-mutant PDAC, were susceptible to concurrent inhibition of ERK-MAPK signaling and of autophagy. Our results uncover phenotypic heterogeneity among KRASQ61 mutants and support the potential utility of therapeutic strategies that target KRASQ61 mutant-specific signaling and cellular output.
    DOI:  https://doi.org/10.1126/scisignal.abn2694
  9. Cancer Res. 2022 Aug 11. pii: CAN-22-1742. [Epub ahead of print]
    Systematic comparison of pancreatic ductal adenocarcinoma models identifies a conserved highly plastic basal cell state.
    Kenneth L Pitter, Olivera Grbovic-Huezo, Simon Joost, Anupriya Singhal, Melissa Blum, Katherine Wu, Matilda Holm, Alexander Ferrena, Arjun Bhutkar, Anna Hudson, Nicolas Lecomte, Elisa de Stanchina, Ronan Chaligne, Christine A Iacobuzio-Donahue, Dana Pe'er, Tuomas Tammela.
      Intra-tumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including pancreatic ductal adenocarcinoma (PDAC). As PDAC portends a dire prognosis, a better understanding of the mechanisms underpinning cellular diversity in PDAC is crucial. Here, we investigated the cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics. Heterogeneity contracted significantly in 2D and 3D cell culture models but was restored upon orthotopic transplantation. Orthotopic transplants reproducibly acquired cell states identified in autochthonous PDAC tumors, including a basal state exhibiting co-expression and co-accessibility of epithelial and mesenchymal genes. Lineage-tracing combined with single-cell transcriptomics revealed that basal cells display high plasticity in situ. This work defines the impact of cellular growth conditions on phenotypic diversity and uncovers a highly plastic cell state with the capacity to facilitate state transitions and promote intra-tumoral heterogeneity in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1742
  10. Cancers (Basel). 2022 Jul 31. pii: 3737. [Epub ahead of print]14(15):
    Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition.
    Stefania Cannone, Maria Raffaella Greco, Tiago M A Carvalho, Helene Guizouarn, Olivier Soriani, Daria Di Molfetta, Richard Tomasini, Katrine Zeeberg, Stephan Joel Reshkin, Rosa Angela Cardone.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancers, having one of the lowest five-year survival rates. One of its hallmarks is a dense desmoplastic stroma consisting in the abnormal accumulation of extracellular matrix (ECM) components, especially Collagen I. This highly fibrotic stroma embeds the bulk cancer (parenchymal) cells (CPCs), cancer stem cells (CSCs) and the main producers of the stromal reaction, the Cancer Associated Fibroblasts (CAFs). Little is known about the role of the acellular ECM in the interplay of the CAFs with the different tumor cell types in determining their phenotypic plasticity and eventual cell fate.METHODS: Here, we analyzed the role of ECM collagen I in modulating the effect of CAF-derived signals by incubating PDAC CPCs and CSCs grown on ECM mimicking early (low collagen I levels) and late (high collagen I levels) stage PDAC stroma with conditioned medium from primary cultured CAFs derived from patients with PDAC in a previously described three-dimensional (3D) organotypic model of PDAC.
    RESULTS: We found that CAFs (1) reduced CPC growth while favoring CSC growth independently of the ECM; (2) increased the invasive capacity of only CPCs on the ECM mimicking the early tumor; and (3) favored vasculogenic mimicry (VM) especially of the CSCs on the ECM mimicking an early tumor.
    CONCLUSIONS: We conclude that the CAFs and acellular stromal components interact to modulate the tumor behaviors of the PDAC CPC and CSC cell types and drive metastatic progression by stimulating the phenotypic characteristics of each tumor cell type that contribute to metastasis.
    Keywords:  3D organotypic cultures; desmoplastic reaction; invadopodia; pancreatic ductal adenocarcinoma; vasculogenic mimicry
    DOI:  https://doi.org/10.3390/cancers14153737
  11. Nat Med. 2022 Aug 11.
    Cellular senescence and senolytics: the path to the clinic.
    Selim Chaib, Tamar Tchkonia, James L Kirkland.
      Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies-including recent and ongoing clinical trials-for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.
    DOI:  https://doi.org/10.1038/s41591-022-01923-y
  12. Matrix Biol. 2022 Aug 05. pii: S0945-053X(22)00096-8. [Epub ahead of print]
    Chemotherapy treatment induces pro-invasive changes in liver ECM composition.
    Justinne R Guarin, Jackson P Fatherree, Madeleine J Oudin.
      Metastasis accounts for 90% of cancer-related deaths, yet the mechanisms by which cancer cells colonize secondary organs remain poorly understood. For breast cancer patients, metastasis to the liver is associated with poor prognosis and a median survival of 6 months. Standard of care is chemotherapy, but recurrence occurs in 30% of patients. Systemic chemotherapy has been shown to induce hepatotoxicity and fibrosis, but how chemotherapy impacts the composition of the liver extracellular matrix (ECM) remains unknown. Individual ECM proteins drive tumor cell proliferation and invasion, features that are essential for metastatic outgrowth in the liver. First, we find that the ECM of livers isolated from chemotherapy-treated MMTV-PyMT mice increases the invasion, but not proliferation, of metastatic breast cancer cells. Proteomic analysis of the liver ECM identified Collagen V to be more abundant in paclitaxel-treated livers. We show that Collagen V increases cancer cell invasion via α1β1 integrins and MAPK signaling, while also increasing the alignment of Collagen I, which has been associated with increased invasion. Treatment with obtustatin, an inhibitor specific to α1β1 integrins, inhibits tumor cell invasion in decellularized ECM from paclitaxel-treated livers. Overall, we show chemotherapy treatment alters the liver microenvironment, priming it as a pro-metastatic niche for cancer metastasis.
    Keywords:  Breast Cancer; Chemotherapy; Collagens; Liver; Metastasis; Migration
    DOI:  https://doi.org/10.1016/j.matbio.2022.08.002
  13. J Exp Clin Cancer Res. 2022 Aug 10. 41(1): 241
    CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer.
    Siyuan Zeng, Bin Lan, Xiaofan Ren, Shuman Zhang, Daniel Schreyer, Markus Eckstein, Hai Yang, Nathalie Britzen-Laurent, Andreas Dahl, Debabrata Mukhopadhyay, David Chang, Isabella Kutschick, Susanne Pfeffer, Peter Bailey, Andrew Biankin, Robert Grützmann, Christian Pilarsky.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance remain as severe hurtles towards improved prognosis. Thus, new therapeutic targets and innovative strategies are urgently needed.METHODS: In this study, we used the KPC mouse model-derived PDAC cell line TB32047 to perform kinome-wide CRISPR-Cas9 loss-of-function screening. Next-generation sequencing and MAGeCK-VISPR analysis were performed to identify candidate genes. We then conducted cell viability, clonogenic, and apoptosis assays and evaluated the synergistic therapeutic effects of cyclin-dependent kinase 7 (CDK7) depletion or inhibition with gemcitabine (GEM) and paclitaxel (PTX) in a murine orthotopic pancreatic cancer model. For mechanistic studies, we performed genome enrichment analysis (GSEA) and Western blotting to identify and verify the pathways that render PDAC sensitive to GEM/PTX therapy.
    RESULTS: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, CDK7 ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction, and DNA damage at least predominantly through the STAT3-MCL1-CHK1 axis. Furthermore, THZ1 synergized with GEM and PTX in vitro and in vivo, resulting in enhanced antitumor effects.
    CONCLUSIONS: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and suggest new strategies for overcoming chemoresistance in pancreatic cancer.
    Keywords:  CDK7; CRISPR-Cas9; FOLFIRINOX; Gemcitabine; Paclitaxel; THZ1
    DOI:  https://doi.org/10.1186/s13046-022-02443-w
  14. Cancer Res. 2022 Aug 11. pii: CAN-22-0018. [Epub ahead of print]
    Targeting Plk1 sensitizes pancreatic cancer to immune checkpoint therapy.
    Zhuangzhuang Zhang, Lijun Cheng, Jie Li, Qi Qiao, Anju Karki, Derek B Allison, Nuha Shaker, Kunyu Li, Sagar M Utturkar, Nadia M Atallah Lanman, Xiongjian Rao, Piotr Rychahou, Daheng He, Stephen F Konieczny, Chi Wang, Qing Shao, B Mark Evers, Xiaoqi Liu.
      Polo-like kinase 1 (Plk1) plays an important role in cell cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in PDAC patients. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NFκB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NFκB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an anti-tumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NFκB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0018
  15. Molecules. 2022 Jul 27. pii: 4811. [Epub ahead of print]27(15):
    MALDI-MSI: A Powerful Approach to Understand Primary Pancreatic Ductal Adenocarcinoma and Metastases.
    Juliana Pereira Lopes Gonçalves, Christine Bollwein, Anna Melissa Schlitter, Mark Kriegsmann, Anne Jacob, Wilko Weichert, Kristina Schwamborn.
      Cancer-related deaths are very commonly attributed to complications from metastases to neighboring as well as distant organs. Dissociate response in the treatment of pancreatic adenocarcinoma is one of the main causes of low treatment success and low survival rates. This behavior could not be explained by transcriptomics or genomics; however, differences in the composition at the protein level could be observed. We have characterized the proteomic composition of primary pancreatic adenocarcinoma and distant metastasis directly in human tissue samples, utilizing mass spectrometry imaging. The mass spectrometry data was used to train and validate machine learning models that could distinguish both tissue entities with an accuracy above 90%. Model validation on samples from another collection yielded a correct classification of both entities. Tentative identification of the discriminative molecular features showed that collagen fragments (COL1A1, COL1A2, and COL3A1) play a fundamental role in tumor development. From the analysis of the receiver operating characteristic, we could further advance some potential targets, such as histone and histone variations, that could provide a better understanding of tumor development, and consequently, more effective treatments.
    Keywords:  mass spectrometry imaging; metastasis; pancreatic ductal adenocarcinoma; prognosis; proteomics; tumor development
    DOI:  https://doi.org/10.3390/molecules27154811
  16. Oncogene. 2022 Aug 10.
    BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.
    Brian Diskin, Salma Adam, Gustavo Sanchez Soto, Miguel Liria, Berk Aykut, Belen Sundberg, Eric Li, Joshua Leinwand, Ruonan Chen, Mirhee Kim, Ruben D Salas, Marcelo F Cassini, Chandan Buttar, Wei Wang, Mohammad Saad Farooq, Sorin A A Shadaloey, Gregor Werba, Amreek Fnu, Fan Yang, Carolina Hirsch, John Glinski, Angilee Panjwani, Yael Weitzner, Deirdre Cohen, George Miller.
      Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.
    DOI:  https://doi.org/10.1038/s41388-022-02425-4
  17. J Cell Sci. 2022 Aug 01. pii: jcs259355. [Epub ahead of print]135(15):
    Exploring cell and tissue mechanics with optical tweezers.
    Frederic Català-Castro, Erik Schäffer, Michael Krieg.
      Cellular and tissue biosystems emerge from the assembly of their constituent molecules and obtain a set of specific material properties. To measure these properties and understand how they influence cellular function is a central goal of mechanobiology. From a bottoms-up, physics or engineering point-of-view, such systems are a composition of basic mechanical elements. However, the sheer number and dynamic complexity of them, including active molecular machines and their emergent properties, makes it currently intractable to calculate how biosystems respond to forces. Because many diseases result from an aberrant mechanotransduction, it is thus essential to measure this response. Recent advances in the technology of optical tweezers have broadened their scope from single-molecule applications to measurements inside complex cellular environments, even within tissues and animals. Here, we summarize the basic optical trapping principles, implementations and calibration procedures that enable force measurements using optical tweezers directly inside cells of living animals, in combination with complementary techniques. We review their versatility to manipulate subcellular organelles and measure cellular frequency-dependent mechanics in the piconewton force range from microseconds to hours. As an outlook, we address future challenges to fully unlock the potential of optical tweezers for mechanobiology.
    Keywords:  Cell mechanics; Forces; Mechanobiology; Optical tweezer; Rheology
    DOI:  https://doi.org/10.1242/jcs.259355
  18. Oncogenesis. 2022 Aug 09. 11(1): 46
    Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance.
    Sophie Vasseur, Fabienne Guillaumond.
      Lipids are essential constituents for malignant tumors, as they are absolutely required for tumor growth and dissemination. Provided by the tumor microenvironment (TME) or by cancer cells themselves through activation of de novo synthesis pathways, they orchestrate a large variety of pro-tumorigenic functions. Importantly, TME cells, especially immune cells, cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs), are also prone to changes in their lipid content, which hinder or promote tumor aggressiveness. In this review, we address the significant findings for lipid contribution in tumor progression towards a metastatic disease and in the poor response to therapeutic treatments. We also highlight the benefits of targeting lipid pathways in preclinical models to slow down metastasis development and overcome chemo-and immunotherapy resistance.
    DOI:  https://doi.org/10.1038/s41389-022-00420-8
  19. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Jul 22.
    Skin manifestations of pancreatic diseases.
    Lumir Kunovsky, Petr Dite, Eva Brezinova, Libuse Sedlakova, Jan Trna, Petr Jabandziev.
      Although symptoms of pancreatic diseases such as pancreatitis, acute and chronic and, carcinoma of the pancreas are mainly gastrointestinal in nature, the extra-pancreatic symptoms are also important. These include skin symptoms, such as pancreatic panniculitis, acanthosis nigricans, livedo reticularis, necrolytic migratory erythema, cutaneous signs of hemorrhage, as in persons with severe acute pancreatitis, or the finding of cutaneous metastases of pancreatic carcinoma, which may be a sign of advanced disease. The pancreas is therefore one of those organs for which diagnosis and therapy are often multidisciplinary. In this review article, we summarize current knowledge of the possible skin manifestations of pancreatic disorders.
    Keywords:  acanthosis nigricans; acute pancreatitis; chronic pancreatitis; livedo reticularis; necrolytic migratory erythema; pancreatic cancer; pancreatic panniculitis; skin lesions
    DOI:  https://doi.org/10.5507/bp.2022.035
  20. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00708-0. [Epub ahead of print]
    Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.
    Jacob M Winter, Tarun Yadav, Jared Rutter.
      Mitochondrial energetics and respiration have emerged as important factors in how cancer cells respond to or evade apoptotic signals. The study of the functional connection between these two processes may provide insight into following questions old and new: how might we target respiration or downstream signaling pathways to amplify apoptotic stress in the context of cancer therapy? Why are respiration and apoptotic regulation housed in the same organelle? Here, we briefly review mitochondrial respiration and apoptosis and then focus on how the intersection of these two processes is regulated by cytoplasmic signaling pathways such as the integrated stress response.
    Keywords:  CRISPR; apoptosis; cancer; electron transport chain; integrated stress response; leukemia; mitochondria; oncology; oxidative phosphorylation; respiration; stress; venetoclax
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.012
  21. Sci Rep. 2022 Aug 10. 12(1): 13592
    Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis.
    Pedro Luiz Serrano Uson Junior, Leonardo Carvalho, Milena Lourenço Coleta Fernandes, Gehan Botrus, Rodrigo de Souza Martins, Elaine Ferreira da Silva, Sarah Silva Mello Batista Dos Santos, Leticia Taniwaki, Patrícia Taranto, Ana Carolina Pereira Dutra, João Bosco de Oliveira Filho, Sergio Eduardo Alonso Araujo, Fernando Moura.
      Neoadjuvant chemotherapy is considered a new treatment option for potentially resectable pancreatic cancer. However, data are not well established on overall survival and delaying surgery in resectable pancreatic cancer, as well as on those patients that ultimately cannot undergo surgery. We analyzed pancreatic cancer patients treated in a tertiary hospital from January 2016 to December 2020. Patients with resectable stage I and II pancreatic cancer were evaluated regarding surgery, neoadjuvant treatment, and other clinical demographics. The survival function was estimated using the Kaplan-Meier method, and the relationship between the variables of interest and the overall survival (OS) was assessed by adopting the proportional regression Cox models. A total of 216 patients were evaluated. 81 of them with resectable/borderline resectable disease and 135 with unresectable /metastatic disease at diagnosis. Median OS for stage I and II disease were 36 and 28 months, respectively. For resectable pancreatic cancer median OS was 28 months, for borderline resectable pancreatic cancer median OS was 11 months. Median OS for stage III (locally advanced) and stage IV (metastatic) were 10 and 7 months, respectively (p < 0.0001). Median OS of 9 months were obtained for patients with stage I and II that did not undergo surgery compared to 25 months in patients that underwent surgery in any time (p < 0.001). Comparing patients with localized disease, median OS for patients treated with upfront surgery was 28 months, compared to 15 months in patients treated with neoadjuvant approach (p = 0.04). Most patients that did not undergo surgery have decline of performance status or disease progression on neoadjuvant treatment. On multivariable analysis in pancreatic cancer stages I and II, including age, sex, borderline or resectable disease, CA 19-9, positive lymph nodes and neoadjuvant treatment, the surgery was the only factor associated with improved overall survival (p = 0.04). Upfront surgery should still be considered a standard of care approach for resectable pancreatic cancer. Biomarker driven studies and randomized trials with combination therapies are necessary to address neoadjuvant chemotherapy and delaying surgery in purely resectable pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41598-022-17743-6
  22. Inflamm Res. 2022 Aug 13.
    Comprehensive comparison of the prognostic value of systemic inflammation biomarkers for cancer cachexia: a multicenter prospective study.
    Hailun Xie, Guotian Ruan, Lishuang Wei, Heyang Zhang, Yizhong Ge, Qi Zhang, Shiqi Lin, Mengmeng Song, Xi Zhang, Xiaoyue Liu, Ming Yang, Meng Tang, Chun-Hua Song, Li Deng, Hanping Shi.
      AIMS: Systemic inflammation plays an important role in cancer cachexia. However, among the systemic inflammatory biomarkers, it is unclear which has optimal prognostic value for cancer cachexia.METHODS: The Kaplan-Meier method was used and the log-rank analysis was performed to estimate survival differences between groups. Cox proportional hazard regression analyses were conducted to assess independent risk factors for all-cause mortality.
    RESULTS: The C-reactive protein-to-albumin ratio (CAR) was the optimal prognostic assessment tool for patients with cancer cachexia, with 1-, 3-, and 5-year predictive powers of 0.650, 0.658, and 0.605, respectively. Patients with a high CAR had significantly lower survival rates than those with a low CAR. Moreover, CAR can differentiate the prognoses of patients with the same pathological stage. Cox proportional risk regression analyses showed that a high CAR was an independent risk factor for cancer cachexia. For every standard deviation increase in CAR, the risk of poor prognosis for patients with cancer cachexia was increased by 20% (hazard ratio = 1.200, 95% confidence interval = 1.132-1.273, P < 0.001).
    CONCLUSIONS: CAR is an effective representative of systemic inflammation and a powerful factor for predicting the life function and clinical outcome of patients with cancer cachexia.
    Keywords:  Biomarker; Cachexia; Cancer; Systemic inflammation
    DOI:  https://doi.org/10.1007/s00011-022-01626-7
  23. Am J Physiol Heart Circ Physiol. 2022 Aug 12.
    The importance of biological sex in cardiac cachexia.
    Ethan R Holder, Faisal J Alibhai, Samantha L Caudle, John C McDermott, Stephanie W Tobin.
      Cardiac cachexia is a catabolic muscle wasting syndrome observed in approximately 1 in 10 heart failure patients. Increased skeletal muscle atrophy leads to frailty and limits mobility which impacts quality of life, exacerbates clinical care, and is associated with higher rates of mortality. Heart failure is known to exhibit a wide range of prevalence and severity when examined across individuals of different ages and with co-morbidities related to diabetes, renal failure and pulmonary dysfunction. It is also recognized that men and women exhibit striking differences in the pathophysiology of heart failure as well as skeletal muscle homeostasis. Given that both skeletal muscle and heart failure physiology are in-part sex dependent, the diagnosis and treatment of cachexia in heart failure patients may depend on a comprehensive examination of how these organs interact. In this review we explore the potential for sex-specific differences in cardiac cachexia. We summarize advantages and disadvantages of clinical methods used to measure muscle mass and function and provide alternative measurements that should be considered in preclinical studies. Additionally, we summarize sex-dependent effects on muscle wasting in preclinical models of heart failure, disuse, and cancer. Lastly, we discuss the endocrine function of the heart and outline unanswered questions that could directly impact patient care.
    Keywords:  cachexia; estrogen; heart failure; muscle wasting; sex
    DOI:  https://doi.org/10.1152/ajpheart.00187.2022
  24. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041261. [Epub ahead of print]
    Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
    Ana Paula Arruda, Güneş Parlakgül.
      The endoplasmic reticulum (ER) is a key organelle involved in the regulation of lipid and glucose metabolism, proteostasis, Ca2+ signaling, and detoxification. The structural organization of the ER is very dynamic and complex, with distinct subdomains such as the nuclear envelope and the peripheral ER organized into ER sheets and tubules. ER also forms physical contact sites with all other cellular organelles and with the plasma membrane. Both form and function of the ER are highly adaptive, with a potent capacity to respond to transient changes in environmental cues such as nutritional fluctuations. However, under obesity-induced chronic stress, the ER fails to adapt, leading to ER dysfunction and the development of metabolic pathologies such as insulin resistance and fatty liver disease. Here, we discuss how the remodeling of ER structure and contact sites with other organelles results in diversification of metabolic function and how perturbations to this structural flexibility by chronic overnutrition contribute to ER dysfunction and metabolic pathologies in obesity.
    DOI:  https://doi.org/10.1101/cshperspect.a041261
  25. Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00132-6. [Epub ahead of print] 101563
    Impact of metabolic stress induced by diets, aging and fasting on tissue oxygen consumption.
    Olena Mackert, Eva Katrin Wirth, Rongwan Sun, Jennifer Winkler, Aoxue Liu, Kostja Renko, Séverine Kunz, Joachim Spranger, Sebastian Brachs.
      OBJECTIVE: Alterations in mitochondrial function play an important role in the development of various diseases, such as obesity, insulin resistance, steatohepatitis, atherosclerosis and cancer. However, accurate assessment of mitochondrial respiration ex vivo is limited and remains highly challenging. Using our novel method, we measured mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of metabolically relevant tissues ex vivo to investigate the impact of different metabolic stressors on mitochondrial function.METHODS: Comparative analysis of OCR and ECAR in young mice fed either 12 weeks high-fat (HFD), high-sucrose (HSD), or western diet (WD), a HFD in matured mice, 2 years prolonged aging on standard-control diet (STD), as well as fasting in tissue biopsies.
    RESULTS: While diets had only marginal effects on mitochondrial respiration, respiratory chain complexes II and IV were reduced. Moreover, matured HFD-fed mice showed a decreased hepatic metabolic flexibility and prolonged aging increased OCR in brown adipose tissue. Interestingly, fasting boosted pancreatic and hepatic OCR while decreasing weight of those organs. Furthermore, ECAR measurements in adipose tissue could indicate its lipolytic capacity.
    CONCLUSION: Using ex vivo tissue measurements, we could extensively analyze mitochondrial function of liver, adipose tissue, pancreas and heart revealing effects of metabolic stress, especially aging.
    Keywords:  age; diet; fasting; metabolic stress; mitochondrial respiration; oxygen consumption rate
    DOI:  https://doi.org/10.1016/j.molmet.2022.101563
  26. Nat Metab. 2022 Aug 08.
    Introducing the Lipidomics Minimal Reporting Checklist.
    Jeffrey G McDonald, Christer S Ejsing, Dominik Kopczynski, Michal Holčapek, Junken Aoki, Makoto Arita, Masanori Arita, Erin S Baker, Justine Bertrand-Michel, John A Bowden, Britta Brügger, Shane R Ellis, Maria Fedorova, William J Griffiths, Xianlin Han, Jürgen Hartler, Nils Hoffmann, Jeremy P Koelmel, Harald C Köfeler, Todd W Mitchell, Valerie B O'Donnell, Daisuke Saigusa, Dominik Schwudke, Andrej Shevchenko, Candice Z Ulmer, Markus R Wenk, Michael Witting, Denise Wolrab, Yu Xia, Robert Ahrends, Gerhard Liebisch, Kim Ekroos.
      
    DOI:  https://doi.org/10.1038/s42255-022-00628-3
  27. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041254. [Epub ahead of print]
    Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes.
    Takuo Osawa, Kazuaki Matoba, Nobuo N Noda.
      Autophagy is an intracellular degradation system involving de novo generation of autophagosomes, which function as a transporting vesicle of cytoplasmic components to lysosomes for degradation. Isolation membranes (IMs) or phagophores, the precursor membranes of autophagosomes, require millions of phospholipids to expand and transform into autophagosomes, with the endoplasmic reticulum (ER) being the primary lipid source. Recent advances in structural and biochemical studies of autophagy-related proteins have revealed their lipid transport activities: Atg2 at the interface between IM and ER possesses intermembrane lipid transfer activities, while Atg9 at IM and VMP1 and TMEM41B at ER possess lipid scrambling activities. In this review, we summarize recent advances in the establishment of the lipid transport activities of these proteins and their collaboration mechanisms for lipid transport between the ER and IM, and further discuss how unidirectional lipid transport from the ER to IM occurs during autophagosome formation.
    DOI:  https://doi.org/10.1101/cshperspect.a041254
  28. Int J Comput Assist Radiol Surg. 2022 Aug 11.
    Artificial intelligence for the detection of pancreatic lesions.
    Julia Arribas Anta, Iván Martínez-Ballestero, Daniel Eiroa, Javier García, Júlia Rodríguez-Comas.
      PURPOSE: Pancreatic cancer is one of the most lethal neoplasms among common cancers worldwide, and PCLs are well-known precursors of this type of cancer. Artificial intelligence (AI) could help to improve and speed up the detection and classification of pancreatic lesions. The aim of this review is to summarize the articles addressing the diagnostic yield of artificial intelligence applied to medical imaging (computed tomography [CT] and/or magnetic resonance [MR]) for the detection of pancreatic cancer and pancreatic cystic lesions.METHODS: We performed a comprehensive literature search using PubMed, EMBASE, and Scopus (from January 2010 to April 2021) to identify full articles evaluating the diagnostic accuracy of AI-based methods processing CT or MR images to detect pancreatic ductal adenocarcinoma (PDAC) or pancreatic cystic lesions (PCLs).
    RESULTS: We found 20 studies meeting our inclusion criteria. Most of the AI-based systems used were convolutional neural networks. Ten studies addressed the use of AI to detect PDAC, eight studies aimed to detect and classify PCLs, and 4 aimed to predict the presence of high-grade dysplasia or cancer.
    CONCLUSION: AI techniques have shown to be a promising tool which is expected to be helpful for most radiologists' tasks. However, methodologic concerns must be addressed, and prospective clinical studies should be carried out before implementation in clinical practice.
    Keywords:  Artificial intelligence; Pancreatic cancer; Pancreatic cystic lesions
    DOI:  https://doi.org/10.1007/s11548-022-02706-z
  29. Cells. 2022 Jul 27. pii: 2317. [Epub ahead of print]11(15):
    Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology.
    Irina Kareva.
      Cancer cachexia is one of the leading causes of mortality for late-stage cancer patients. One of its key characteristics is abnormal metabolism and loss of metabolic flexibility, i.e., loss of ability to switch between use of fats and carbohydrates as needed. Here, it is hypothesized that late-stage systemic cancer creates a chronic resource drain on the body that may result in the same metabolic adaptations that occur during intense endurance exercise, activating some of the same mechanisms of nutrient consumption that are supposed to be transient during strenuous physical activity. This hypothesis is evaluated by creating a mathematical model that characterizes the relationships between increased exercise intensity and carbohydrate and fat oxidation. The model is parametrized using published data on these characteristics for a group of professional athletes, moderately active individuals, and individuals with metabolic syndrome. Transitions between different zones of relative nutrient consumption as a function of increased effort are captured through explicitly modeling ventilatory thresholds, particularly VT1 and VT2, where fat is primarily used below VT1, both carbohydrates and fats are used between VT1 and VT2, and where carbohydrates become the primary source of fuel above VT2. A simulation is conducted of projected patterns of nutrient consumption when simulated "effort" remains between VT1 and VT2, or above VT2, and it is proposed that it is the scenario when the simulated effort is maintained primarily above VT2 that most closely resembles metabolic patterns characteristic of cachexia. A discussion of a broader framework for understanding cachectic metabolism using insights from exercise physiology, including potential intervention strategies, concludes this paper.
    Keywords:  cachexia; cancer; metabolic derangement; metabolic flexibility; metabolism; ventilatory thresholds
    DOI:  https://doi.org/10.3390/cells11152317
  30. Science. 2022 Aug 12. 377(6607): 712-713
    Activating translation with phase separation.
    Anne Ramat, Martine Simonelig.
      Ribonucleoprotein granules allow activation of translation to complete mouse spermatogenesis.
    DOI:  https://doi.org/10.1126/science.add6323
  31. STAR Protoc. 2022 Sep 16. 3(3): 101586
    Analysis of germline-driven ancestry-associated gene expression in cancers.
    Cancer Genome Analysis Network
      Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enumerate ancestry-informative markers colocalized with cancer-type-specific expression quantitative trait loci (e-QTLs) at ancestry-associated genes. This approach is generalizable to other settings with paired germline genotyping and mRNA expression data for a multi-ethnic cohort. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020), Robertson et al. (2021), and Sayaman et al. (2021).
    Keywords:  Bioinformatics; Cancer; Computer sciences; Gene Expression; Genomics; RNAseq; Sequence analysis
    DOI:  https://doi.org/10.1016/j.xpro.2022.101586
  32. Nat Rev Cancer. 2022 Aug 08.
    Cancer nanomedicine.
    Sangeeta N Bhatia, Xiaoyuan Chen, Marina A Dobrovolskaia, Twan Lammers.
      
    DOI:  https://doi.org/10.1038/s41568-022-00496-9
  33. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00647-5. [Epub ahead of print]
    Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
    Consuelo Torrini, Trang Thi Thu Nguyen, Chang Shu, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Erin Heather Seeley, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.
      Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.
    Keywords:  ATAC-seq; ChIP-seq; glioblastoma; lactate; metabolic flux analysis; tumor metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.030
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