bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒11‒13
35 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis.
  2. Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1.
  3. Interleukin-6 initiates muscle- and adipose tissue wasting in a novel C57BL/6 model of cancer-associated cachexia.
  4. NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
  5. Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer.
  6. ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
  7. GJB3 promotes pancreatic cancer liver metastasis by enhancing the polarization and survival of neutrophil.
  8. Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.
  9. Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
  10. Spatial genomics maps the structure, nature and evolution of cancer clones.
  11. Mechanisms of cancer metastasis.
  12. Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
  13. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
  14. Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
  15. How cells recognize and remove the perforated lysosome.
  16. The phenotypic landscape of essential human genes.
  17. Mutations in the α4-α5 allosteric lobe of RAS do not significantly impair RAS signaling or self-association.
  18. The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
  19. Oxaliplatin disrupts nucleolar function through biophysical disintegration.
  20. Quantitative Framework for Bench-to-Bedside Cancer Research.
  21. Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-mutant Pancreatic Cancer.
  22. TriMem: A parallelized hybrid Monte Carlo software for efficient simulations of lipid membranes.
  23. OrganoID: A versatile deep learning platform for tracking and analysis of single-organoid dynamics.
  24. Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation.
  25. The Evolving Landscape of Pancreatic Cancer.
  26. Subcellular Redox Responses Reveal Different Cu-dependent Antioxidant Defenses between Mitochondria and Cytosol.
  27. Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization.
  28. Molecular characterization of acquired resistance to KRAS G12C-EGFR inhibition in colorectal cancer.
  29. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity.
  30. Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry.
  31. Nomogram for Predicting Distant Metastasis of Pancreatic Ductal Adenocarcinoma: A SEER-Based Population Study.
  32. PI(4,5)P2: signaling the plasma membrane.
  33. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
  34. Proteolytic and mechanical remodeling of the extracellular matrix by invadopodia in cancer.
  35. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.
  1. Nat Cancer. 2022 Nov 07.
    MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis.
    Francisco M Barriga, Kaloyan M Tsanov, Yu-Jui Ho, Noor Sohail, Amy Zhang, Timour Baslan, Alexandra N Wuest, Isabella Del Priore, Brigita Meškauskaitė, Geulah Livshits, Direna Alonso-Curbelo, Janelle Simon, Almudena Chaves-Perez, Dafna Bar-Sagi, Christine A Iacobuzio-Donahue, Faiyaz Notta, Ronan Chaligne, Roshan Sharma, Dana Pe'er, Scott W Lowe.
      The most prominent homozygous deletions in cancer affect chromosome 9p21.3 and eliminate CDKN2A/B tumor suppressors, disabling a cell-intrinsic barrier to tumorigenesis. Half of 9p21.3 deletions, however, also encompass a type I interferon (IFN) gene cluster; the consequences of this co-deletion remain unexplored. To functionally dissect 9p21.3 and other large genomic deletions, we developed a flexible deletion engineering strategy, MACHETE (molecular alteration of chromosomes with engineered tandem elements). Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we found that co-deletion of the IFN cluster promoted immune evasion, metastasis and immunotherapy resistance. Mechanistically, IFN co-deletion disrupted type I IFN signaling in the tumor microenvironment, leading to marked changes in infiltrating immune cells and escape from CD8+ T-cell surveillance, effects largely driven by the poorly understood interferon epsilon. These results reveal a chromosomal deletion that disables both cell-intrinsic and cell-extrinsic tumor suppression and provide a framework for interrogating large deletions in cancer and beyond.
    DOI:  https://doi.org/10.1038/s43018-022-00443-5
  2. Oncogene. 2022 Nov 10.
    Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1.
    Abigail S Coetzee, Edward P Carter, Lucía Rodríguez-Fernández, James Heward, Qiaoying Wang, Saadia A Karim, Lina Boughetane, Christopher Milton, Firat Uyulur, Jennifer P Morton, Hemant M Kocher, Richard P Grose.
      Pancreatic stellate cells (PSCs) are key to the treatment-refractory desmoplastic phenotype of pancreatic ductal adenocarcinoma (PDAC) and have received considerable attention as a stromal target for cancer therapy. This approach demands detailed understanding of their pro- and anti-tumourigenic effects. Interrogating PSC-cancer cell interactions in 3D models, we identified nuclear FGFR1 as critical for PSC-led invasion of cancer cells. ChIP-seq analysis of FGFR1 in PSCs revealed a number of FGFR1 interaction sites within the genome, notably NRG1, which encodes the ERBB ligand Neuregulin. We show that nuclear FGFR1 regulates transcription of NRG1, which in turn acts in autocrine fashion through an ERBB2/4 heterodimer to promote invasion. In support of this, recombinant NRG1 in 3D model systems rescued the loss of invasion incurred by FGFR inhibition. In vivo we demonstrate that, while FGFR inhibition does not affect the growth of pancreatic tumours in mice, local invasion into the pancreas is reduced. Thus, FGFR and NRG1 may present new stromal targets for PDAC therapy.
    DOI:  https://doi.org/10.1038/s41388-022-02513-5
  3. J Cachexia Sarcopenia Muscle. 2022 Nov 09.
    Interleukin-6 initiates muscle- and adipose tissue wasting in a novel C57BL/6 model of cancer-associated cachexia.
    Isabella Pototschnig, Ursula Feiler, Clemens Diwoky, Paul W Vesely, Thomas Rauchenwald, Margret Paar, Latifa Bakiri, Laura Pajed, Peter Hofer, Karl Kashofer, Nyamdelger Sukhbaatar, Gabriele Schoiswohl, Thomas Weichhart, Gerald Hoefler, Christoph Bock, Martin Pichler, Erwin F Wagner, Rudolf Zechner, Martina Schweiger.
      BACKGROUND: Cancer-associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease-specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic- and non-cachexigenic tumours.METHODS: MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10-11-week-old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical-, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and -composition, food- and water intake, locomotor activity, O2 consumption, CO2 production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high-resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose- and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin-6 (Il-6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing.
    RESULTS: CHX207, but not MCA207-tumour-bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL-6 concentrations (190 pg/mL, P ≤ 0.0001), increased energy expenditure (+28%, P ≤ 0.01), adipose tissue loss (-47%, P ≤ 0.0001), skeletal muscle wasting (-18%, P ≤ 0.001), and body weight reduction (-13%, P ≤ 0.01) 13 days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and -synthesis combined with increased lipolysis but was not associated with elevated beta-adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (-21.8%, P ≤ 0.001), increased catabolic- and reduced anabolic signalling. Deletion of IL-6 from CHX207 cancer cells completely protected CHX207IL6KO -tumour-bearing mice from CAC.
    CONCLUSIONS: In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non-cachectic MCA207-tumour-bearing mice. IL-6 represents an essential trigger for CAC development in CHX207-tumour-bearing mice.
    Keywords:  Adipose tissue; C57BL/6; Cachexia; Cancer; Interleukin-6
    DOI:  https://doi.org/10.1002/jcsm.13109
  4. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01494-2. [Epub ahead of print]41(6): 111623
    NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
    Gopalakrishnan Ramakrishnan, Parash Parajuli, Pura Singh, Creighton Friend, Eric Hurwitz, Celine Prunier, Mohammed S Razzaque, Keli Xu, Azeddine Atfi.
      A long-standing question in the pancreatic ductal adenocarcinoma (PDAC) field has been whether alternative genetic alterations could substitute for oncogenic KRAS mutations in initiating malignancy. Here, we report that Neurofibromin1 (NF1) inactivation can bypass the requirement of mutant KRAS for PDAC pathogenesis. An in-depth analysis of PDAC databases reveals various genetic alterations in the NF1 locus, including nonsense mutations, which occur predominantly in tumors with wild-type KRAS. Genetic experiments demonstrate that NF1 ablation culminates in acinar-to-ductal metaplasia, an early step in PDAC. Furthermore, NF1 haploinsufficiency results in a dramatic acceleration of KrasG12D-driven PDAC. Finally, we show an association between NF1 and p53 that is orchestrated by PML, and mosaic analysis with double markers demonstrates that concomitant inactivation of NF1 and Trp53 is sufficient to trigger full-blown PDAC. Together, these findings open up an exploratory framework for apprehending the mechanistic paradigms of PDAC with normal KRAS, for which no effective therapy is available.
    Keywords:  CP: Cancer; alternative genetic drivers in pancreatic ductal adenocarcinoma; mosaic analysis with double markers; mutant KRAS; pancreatic ductal adenocarcinoma initiation; tumor-suppressor gene NF1; tumor-suppressor gene PML; tumor-suppressor gene TP53
    DOI:  https://doi.org/10.1016/j.celrep.2022.111623
  5. Cancers (Basel). 2022 Oct 28. pii: 5302. [Epub ahead of print]14(21):
    Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer.
    Adam S Bryce, Stephan B Dreyer, Fieke E M Froeling, David K Chang.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.
    Keywords:  PDAC; cancer associated fibroblast; immunotherapy; pancreatic cancer; pancreatic ductal adenocarcinoma; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers14215302
  6. Mol Cell. 2022 Nov 01. pii: S1097-2765(22)01017-6. [Epub ahead of print]
    ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
    Alexander R van Vliet, George N Chiduza, Sarah L Maslen, Valerie E Pye, Dhira Joshi, Stefano De Tito, Harold B J Jefferies, Evangelos Christodoulou, Chloë Roustan, Emma Punch, Javier H Hervás, Nicola O'Reilly, J Mark Skehel, Peter Cherepanov, Sharon A Tooze.
      ATG9A and ATG2A are essential core members of the autophagy machinery. ATG9A is a lipid scramblase that allows equilibration of lipids across a membrane bilayer, whereas ATG2A facilitates lipid flow between tethered membranes. Although both have been functionally linked during the formation of autophagosomes, the molecular details and consequences of their interaction remain unclear. By combining data from peptide arrays, crosslinking, and hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose a molecular model of the ATG9A-2A complex. Using this integrative structure modeling approach, we identify several interfaces mediating ATG9A-2A interaction that would allow a direct transfer of lipids from ATG2A into the lipid-binding perpendicular branch of ATG9A. Mutational analyses combined with functional activity assays demonstrate their importance for autophagy, thereby shedding light on this protein complex at the heart of autophagy.
    Keywords:  AlphaFold; autophagosome; autophagy; integrative structure prediction; lipid scramblase; lipid transfer
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.017
  7. Front Immunol. 2022 ;13 983116
    GJB3 promotes pancreatic cancer liver metastasis by enhancing the polarization and survival of neutrophil.
    Yanmiao Huo, Yaoqi Zhou, Jiahao Zheng, Guangxin Jin, Lingye Tao, Hongfei Yao, Junfeng Zhang, Yongwei Sun, Yingbin Liu, Li-Peng Hu.
      Connexins are membrane expressed proteins, which could assemble into hexamers to transfer metabolites and secondary messengers. However, its roles in pancreatic cancer metastasis remains unknown. In this study, by comparing the gene expression patterns in primary pancreatic cancer patients primary and liver metastasis specimens, we found that Gap Junction Protein Beta 3 (GJB3) significantly increased in Pancreatic ductal adenocarcinoma (PDAC) liver metastasis. Animal experiments verified that GJB3 depletion suppressed the hepatic metastasis of PDAC cancer cells. Further, GJB3 over expression increased the neutrophil infiltration. Mechanistic study revealed that GJB3 form channels between PDAC tumor cells and accumulated neutrophil, which transfer cyclic adenosine monophosphate (cAMP) from cancer to neutrophil cells, which supports the survival and polarization. Taken together, our data suggesting that GJB3 could act as a potential therapeutic target of PDAC liver metastasis.
    Keywords:  GJB3 (Cx31) gene; cAMP; liver metastasis; neutrophil; pancreatic cancer
    DOI:  https://doi.org/10.3389/fimmu.2022.983116
  8. Nature. 2022 Nov 09.
    Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.
    Adrià Cañellas-Socias, Carme Cortina, Xavier Hernando-Momblona, Sergio Palomo-Ponce, Eoghan J Mulholland, Gemma Turon, Lidia Mateo, Sefora Conti, Olga Roman, Marta Sevillano, Felipe Slebe, Diana Stork, Adrià Caballé-Mestres, Antonio Berenguer-Llergo, Adrián Álvarez-Varela, Nicola Fenderico, Laura Novellasdemunt, Laura Jiménez-Gracia, Tamara Sipka, Lidia Bardia, Patricia Lorden, Julien Colombelli, Holger Heyn, Xavier Trepat, Sabine Tejpar, Elena Sancho, Daniele V F Tauriello, Simon Leedham, Camille Stephan-Otto Attolini, Eduard Batlle.
      Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.
    DOI:  https://doi.org/10.1038/s41586-022-05402-9
  9. Cell. 2022 Nov 02. pii: S0092-8674(22)01318-6. [Epub ahead of print]
    Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
    Haopeng Xiao, Luiz H M Bozi, Yizhi Sun, Christopher L Riley, Vivek M Philip, Mandy Chen, Jiaming Li, Tian Zhang, Evanna L Mills, Margo P Emont, Wenfei Sun, Anita Reddy, Ryan Garrity, Jiani Long, Tobias Becher, Laura Potano Vitas, Dina Laznik-Bogoslavski, Martha Ordonez, Xinyue Liu, Xiong Chen, Yun Wang, Weihai Liu, Nhien Tran, Yitong Liu, Yang Zhang, Aaron M Cypess, Andrew P White, Yuchen He, Rebecca Deng, Heiko Schöder, Joao A Paulo, Mark P Jedrychowski, Alexander S Banks, Yu-Hua Tseng, Paul Cohen, Linus T Tsai, Evan D Rosen, Samuel Klein, Maria Chondronikola, Fiona E McAllister, Nick Van Bruggen, Edward L Huttlin, Bruce M Spiegelman, Gary A Churchill, Steven P Gygi, Edward T Chouchani.
      Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
    DOI:  https://doi.org/10.1016/j.cell.2022.10.003
  10. Nature. 2022 Nov 09.
    Spatial genomics maps the structure, nature and evolution of cancer clones.
    Artem Lomakin, Jessica Svedlund, Carina Strell, Milana Gataric, Artem Shmatko, Gleb Rukhovich, Jun Sung Park, Young Seok Ju, Stefan Dentro, Vitalii Kleshchevnikov, Vasyl Vaskivskyi, Tong Li, Omer Ali Bayraktar, Sarah Pinder, Andrea L Richardson, Sandro Santagata, Peter J Campbell, Hege Russnes, Moritz Gerstung, Mats Nilsson, Lucy R Yates.
      Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1-3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.
    DOI:  https://doi.org/10.1038/s41586-022-05425-2
  11. Semin Cancer Biol. 2022 Oct 27. pii: S1044-579X(22)00212-7. [Epub ahead of print]87 17-31
    Mechanisms of cancer metastasis.
    Maria Castaneda, Petra den Hollander, Nick A Kuburich, Jeffrey M Rosen, Sendurai A Mani.
      Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.
    Keywords:  Cancer metastasis; Epithelial-mesenchymal plasticity; Epithelial-mesenchymal transition; Extravasation; Invasion
    DOI:  https://doi.org/10.1016/j.semcancer.2022.10.006
  12. Int J Cancer. 2022 Nov 08.
    Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
    Wei Sun, Erhu Zhao, Hongjuan Cui.
      Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one-carbon units for nucleotide biosynthesis. In this process, serine-glycine metabolism and the one-carbon cycle play vital roles, which is named serine-glycine-one-carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis, and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate-mediated one-carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use one-carbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; drug resistance; inhibitors; serine-glycine-one-carbon metabolism; target enzymes
    DOI:  https://doi.org/10.1002/ijc.34353
  13. Sci Signal. 2022 Nov 08. 15(759): eabj4220
    Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
    Vivien Low, Zhongchi Li, John Blenis.
      The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.
    DOI:  https://doi.org/10.1126/scisignal.abj4220
  14. JCI Insight. 2022 Nov 08. pii: e155147. [Epub ahead of print]
    Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
    Luca J Delfinis, Catherine A Bellissimo, Shivam Gandhi, Sara N DiBenedetto, Madison C Garibotti, Arshdeep K Thuhan, Stavroula Tsitkanou, Megan E Rosa-Caldwell, Fasih A Rahman, Arthur J Cheng, Michael P Wiggs, Uwe Schlattner, Joe Quadrilatero, Nicholas P Greene, Christopher Gr Perry.
      Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 (C26) cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles vs control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress. Eventual muscle-specific restorations in force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.
    Keywords:  Colorectal cancer; Metabolism; Mitochondria; Oncology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.155147
  15. Autophagy. 2022 Nov 11. 1-3
    How cells recognize and remove the perforated lysosome.
    Keisuke Tabata, Marika Saeki, Tamotsu Yoshimori, Maho Hamasaki.
      Macroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria, etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.
    Keywords:  CUL4A; LAMP2; lysophagy; lysosomal membrane damage; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2138686
  16. Cell. 2022 Nov 02. pii: S0092-8674(22)01359-9. [Epub ahead of print]
    The phenotypic landscape of essential human genes.
    Luke Funk, Kuan-Chung Su, Jimmy Ly, David Feldman, Avtar Singh, Brittania Moodie, Paul C Blainey, Iain M Cheeseman.
      Understanding the basis for cellular growth, proliferation, and function requires determining the roles of essential genes in diverse cellular processes, including visualizing their contributions to cellular organization and morphology. Here, we combined pooled CRISPR-Cas9-based functional screening of 5,072 fitness-conferring genes in human HeLa cells with microscopy-based imaging of DNA, the DNA damage response, actin, and microtubules. Analysis of >31 million individual cells identified measurable phenotypes for >90% of gene knockouts, implicating gene targets in specific cellular processes. Clustering of phenotypic similarities based on hundreds of quantitative parameters further revealed co-functional genes across diverse cellular activities, providing predictions for gene functions and associations. By conducting pooled live-cell screening of ∼450,000 cell division events for 239 genes, we additionally identified diverse genes with functional contributions to chromosome segregation. Our work establishes a resource detailing the consequences of disrupting core cellular processes that represents the functional landscape of essential human genes.
    Keywords:  CRISPR-Cas9; cell division; essential genes; functional genomics; high-content screening; in situ sequencing; microscopy; mitosis; morphology; optical pooled screening
    DOI:  https://doi.org/10.1016/j.cell.2022.10.017
  17. J Biol Chem. 2022 Nov 02. pii: S0021-9258(22)01104-8. [Epub ahead of print] 102661
    Mutations in the α4-α5 allosteric lobe of RAS do not significantly impair RAS signaling or self-association.
    Michael Whaby, Lauren Wallon, Megan Mazzei, Imran Khan, Kai Wen Teng, Shohei Koide, John P O'Bryan.
      Mutations in one of the three RAS genes (HRAS, KRAS, and NRAS) are present in nearly 20% of all human cancers. These mutations shift RAS to the GTP-loaded active state due to impairment in the intrinsic GTPase activity and disruption of GAP-mediated GTP hydrolysis, resulting in constitutive activation of effectors such as RAF. Because activation of RAF involves dimerization, RAS dimerization has been proposed as an important step in RAS-mediated activation of effectors. The α4-α5 allosteric lobe of RAS has been proposed as a RAS dimerization interface. Indeed, the NS1 monobody, which binds the α4-α5 region within the RAS G domain, inhibits RAS-dependent signaling and transformation as well as RAS nanoclustering at the plasma membrane. Although these results are consistent with a model in which the G domain dimerizes through the α4-α5 region, the isolated G domain of RAS lacks intrinsic dimerization capacity. Furthermore, prior studies analyzing α4-α5 point mutations have reported mixed effects on RAS function. Here, we evaluated the activity of a panel of single amino acid substitutions in the α4-α5 region implicated in RAS dimerization. We found that these proposed "dimerization-disrupting" mutations do not significantly impair self-association, signaling, or transformation of oncogenic RAS. These results are consistent with a model in which activated RAS protomers cluster in close proximity to promote the dimerization of their associated effector proteins (e.g., RAF) without physically associating into dimers mediated by specific molecular interactions. Our findings suggest the need for a nonconventional approach to developing therapeutics targeting the α4-α5 region.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102661
  18. Biochim Biophys Acta Bioenerg. 2022 Oct 29. pii: S0005-2728(22)00401-7. [Epub ahead of print]1864(1): 148931
    The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
    M Martins Pinto, P Paumard, C Bouchez, S Ransac, S Duvezin-Caubet, J P Mazat, M Rigoulet, A Devin.
      Cancer cells display an altered energy metabolism, which was proposed to be the root of cancer. This early discovery was done by O. Warburg who conducted one of the first studies of tumor cell energy metabolism. Taking advantage of cancer cells that exhibited various growth rates, he showed that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. In this review, we discuss of the origin of the decrease in cell respiratory rate, whether the Warburg effect is mandatory for an increased cell proliferation rate, the consequences of this effect on two major players of cell energy metabolism that are ATP and NADH, and the role of the microenvironment in the regulation of cellular respiration and metabolism both in cancer cell and in yeast.
    Keywords:  Cancer; Mitochondria; Oxidative phosphorylation; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148931
  19. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01500-5. [Epub ahead of print]41(6): 111629
    Oxaliplatin disrupts nucleolar function through biophysical disintegration.
    H Broder Schmidt, Zane A Jaafar, B Erik Wulff, Jason J Rodencal, Kibeom Hong, Mohammad O Aziz-Zanjani, Peter K Jackson, Manuel D Leonetti, Scott J Dixon, Rajat Rohatgi, Onn Brandman.
      Platinum (Pt) compounds such as oxaliplatin are among the most commonly prescribed anti-cancer drugs. Despite their considerable clinical impact, the molecular basis of platinum cytotoxicity and cancer specificity remain unclear. Here we show that oxaliplatin, a backbone for the treatment of colorectal cancer, causes liquid-liquid demixing of nucleoli at clinically relevant concentrations. Our data suggest that this biophysical defect leads to cell-cycle arrest, shutdown of Pol I-mediated transcription, and ultimately cell death. We propose that instead of targeting a single molecule, oxaliplatin preferentially partitions into nucleoli, where it modifies nucleolar RNA and proteins. This mechanism provides a general approach for drugging the increasing number of cellular processes linked to biomolecular condensates.
    Keywords:  CP: Cancer; colorectal cancer; drug mechanism; nucleolus; phase separation; transcription/ translation inhibitors
    DOI:  https://doi.org/10.1016/j.celrep.2022.111629
  20. Cancers (Basel). 2022 Oct 26. pii: 5254. [Epub ahead of print]14(21):
    Quantitative Framework for Bench-to-Bedside Cancer Research.
    Aubhishek Zaman, Trever G Bivona.
      Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throughput data and in ready availability of data-intensive technologies, mathematical and quantitative approaches have become increasingly common in bioscience. For instance, a recent shift towards a quantitative description of cells and phenotypes, which is supplanting conventional qualitative descriptions, has generated immense promise and opportunities in the field of bench-to-bedside cancer OMICS, chemical biology and pharmacology. Nevertheless, like any burgeoning field, there remains a lack of shared and standardized framework for quantitative cancer research. Here, in the context of cancer, we present a basic framework and guidelines for bench-to-bedside quantitative research and therapy. We outline some of the basic concepts and their parallel use cases for chemical-protein interactions. Along with several recommendations for assay setup and conditions, we also catalog applications of these quantitative techniques in some of the most widespread discovery pipeline and analytical methods in the field. We believe adherence to these guidelines will improve experimental design, reduce variabilities and standardize quantitative datasets.
    Keywords:  IC50; OMICS; bench-to-bedside; chemical biology; high throughput screen (HTS); quantitative biology
    DOI:  https://doi.org/10.3390/cancers14215254
  21. Cancer Res. 2022 Nov 08. pii: CAN-22-0391. [Epub ahead of print]
    Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-mutant Pancreatic Cancer.
    Craig M Goodwin, Andrew M Waters, Jennifer E Klomp, Sehrish Javaid, Kirsten L Bryant, Clint A Stalnecker, Kristina Drizyte-Miller, Bjoern Papke, Runying Yang, Amber M Amparo, Irem Ozkan-Dagliyan, Elisa Baldelli, Valerie Calvert, Mariaelena Pierobon, Jessica A Sorrentino, Andrew P Beelen, Natalie Bublitz, Mareen Lüthen, Kris C Wood, Emanuel F Petricoin, Christine Sers, Autumn J McRee, Adrienne D Cox, Channing J Der.
      Mutational loss of CDKN2A (encoding p16INK4A) tumor suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, anti-apoptotic signaling, and MYC expression. Based on these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small molecule inhibitor-based approaches. Additionally, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to PDAC patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0391
  22. J Chem Phys. 2022 Nov 07. 157(17): 174801
    TriMem: A parallelized hybrid Monte Carlo software for efficient simulations of lipid membranes.
    Marc Siggel, Sebastian Kehl, Klaus Reuter, Jürgen Köfinger, Gerhard Hummer.
      Lipid membranes are integral building blocks of living cells and perform a multitude of biological functions. Currently, molecular simulations of cellular-scale membrane remodeling processes at atomic resolution are extremely difficult, due to their size, complexity, and the large times-scales on which these processes occur. Instead, elastic membrane models are used to simulate membrane shapes and transitions between them and to infer their properties and functions. Unfortunately, an efficiently parallelized open-source simulation code to do so has been lacking. Here, we present TriMem, a parallel hybrid Monte Carlo simulation engine for triangulated lipid membranes. The kernels are efficiently coded in C++ and wrapped with Python for ease-of-use. The parallel implementation of the energy and gradient calculations and of Monte Carlo flip moves of edges in the triangulated membrane enable us to simulate large and highly curved membrane structures. For validation, we reproduce phase diagrams of vesicles with varying surface-to-volume ratios and area difference. We also compute the density of states to verify correct Boltzmann sampling. The software can be used to tackle a range of large-scale membrane remodeling processes as a step toward cell-scale simulations. Additionally, extensive documentation make the software accessible to the broad biophysics and computational cell biology communities.
    DOI:  https://doi.org/10.1063/5.0101118
  23. PLoS Comput Biol. 2022 Nov;18(11): e1010584
    OrganoID: A versatile deep learning platform for tracking and analysis of single-organoid dynamics.
    Jonathan M Matthews, Brooke Schuster, Sara Saheb Kashaf, Ping Liu, Rakefet Ben-Yishay, Dana Ishay-Ronen, Evgeny Izumchenko, Le Shen, Christopher R Weber, Margaret Bielski, Sonia S Kupfer, Mustafa Bilgic, Andrey Rzhetsky, Savaş Tay.
      Organoids have immense potential as ex vivo disease models for drug discovery and personalized drug screening. Dynamic changes in individual organoid morphology, number, and size can indicate important drug responses. However, these metrics are difficult and labor-intensive to obtain for high-throughput image datasets. Here, we present OrganoID, a robust image analysis platform that automatically recognizes, labels, and tracks single organoids, pixel-by-pixel, in brightfield and phase-contrast microscopy experiments. The platform was trained on images of pancreatic cancer organoids and validated on separate images of pancreatic, lung, colon, and adenoid cystic carcinoma organoids, which showed excellent agreement with manual measurements of organoid count (95%) and size (97%) without any parameter adjustments. Single-organoid tracking accuracy remained above 89% over a four-day time-lapse microscopy study. Automated single-organoid morphology analysis of a chemotherapy dose-response experiment identified strong dose effect sizes on organoid circularity, solidity, and eccentricity. OrganoID enables straightforward, detailed, and accurate image analysis to accelerate the use of organoids in high-throughput, data-intensive biomedical applications.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010584
  24. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01501-7. [Epub ahead of print]41(6): 111630
    Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation.
    Poshen B Chen, Patrick C Fiaux, Kai Zhang, Bin Li, Naoki Kubo, Shan Jiang, Rong Hu, Emma Rooholfada, Sihan Wu, Mengchi Wang, Wei Wang, Graham McVicker, Paul S Mischel, Bing Ren.
      A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute to human diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing to identify enhancers required for cell proliferation and fitness in 10 human cancer cell lines. Our results suggest that the cell fitness enhancers, unlike their target genes, display high cell-type specificity of chromatin features. They typically adopt a modular structure, comprised of activating elements enriched for motifs of oncogenic transcription factors, surrounded by repressive elements enriched for motifs recognized by transcription factors with tumor suppressor functions. We further identify cell fitness enhancers that are selectively accessible in clinical tumor samples, and the levels of chromatin accessibility are associated with patient survival. These results reveal functional enhancers across multiple cancer cell lines, characterize their context-dependent chromatin organization, and yield insights into altered transcription programs in cancer cells.
    Keywords:  CP: Cancer; CP: Molecular biology; cell proliferation; functional enhancer; gene regulation; oncogene
    DOI:  https://doi.org/10.1016/j.celrep.2022.111630
  25. JCO Oncol Pract. 2022 Nov 10. OP2200636
    The Evolving Landscape of Pancreatic Cancer.
    Mridula Krishnan.
      
    DOI:  https://doi.org/10.1200/OP.22.00636
  26. Metallomics. 2022 Nov 11. pii: mfac087. [Epub ahead of print]
    Subcellular Redox Responses Reveal Different Cu-dependent Antioxidant Defenses between Mitochondria and Cytosol.
    Yuteng Zhang, Meng-Hsuan Wen, Guoting Qin, Chengzhi Cai, Tai-Yen Chen.
      Excess intracellular Cu perturbs cellular redox balance and thus causes diseases. However, the relationship between cellular redox status and Cu homeostasis and how such an interplay is coordinated within cellular compartments has not yet been well established. Using combined approaches of organelle-specific redox sensor Grx1-roGFP2 and non-targeted proteomics, we investigate the real-time Cu-dependent antioxidant defenses of mitochondria and cytosol in live HEK293 cells. The Cu-dependent real-time imaging experiments show that CuCl2 treatment results in increased oxidative stress in both cytosol and mitochondria. In contrast, subsequent excess Cu removal by BCS, a Cu chelating reagent, lowers oxidative stress in mitochondria but causes even higher oxidative stress in the cytosol. The proteomic data reveal that several mitochondrial proteins, but not cytosolic ones, undergo significant abundance change under Cu treatments. The proteomic analysis also shows that proteins with significant changes are related to mitochondrial oxidative phosphorylation and glutathione synthesis. The differences in redox behaviors and protein profiles in different cellular compartments reveal distinct mitochondrial and cytosolic response mechanisms upon Cu-induced oxidative stress. These findings provide insights into how redox and Cu homeostasis interplay by modulating specific protein expressions at the subcellular levels, shedding light on understanding the effects of Cu-induced redox misregulation on the diseases.
    Keywords:  Cu-induced oxidative stress; cytosol; glutathione; mitochondria; non-targeted proteomics; organelle-specific redox sensor
    DOI:  https://doi.org/10.1093/mtomcs/mfac087
  27. Sci Adv. 2022 Nov 11. 8(45): eabm9729
    Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization.
    Pradipta Ranjan Rauta, Yuri Mackeyev, Keith Sanders, Joseph B K Kim, Valeria V Gonzalez, Yasmin Zahra, Muhammad A Shohayeb, Belal Abousaida, Geraldine V Vijay, Okan Tezcan, Paul Derry, Anton V Liopo, Eugene R Zubarev, Rickey Carter, Pankaj Singh, Sunil Krishnan.
      Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.
    DOI:  https://doi.org/10.1126/sciadv.abm9729
  28. Cancer Discov. 2022 Nov 10. pii: CD-22-0405. [Epub ahead of print]
    Molecular characterization of acquired resistance to KRAS G12C-EGFR inhibition in colorectal cancer.
    Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J Nanjangud, Michael F Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D Socci, Jinru Shia, Gregory J Riely, Yonina R Murciano-Goroff, Bob T Li, James G Christensen, Jorge S Reis-Filho, David B Solit, Elisa de Stanchina, Scott W Lowe, Neal Rosen, Sandra Misale.
      With the combination of KRAS G12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRAS G12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRAS G12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0405
  29. Nature. 2022 Nov 09.
    Liver tumour immune microenvironment subtypes and neutrophil heterogeneity.
    Ruidong Xue, Qiming Zhang, Qi Cao, Ruirui Kong, Xiao Xiang, Hengkang Liu, Mei Feng, Fangyanni Wang, Jinghui Cheng, Zhao Li, Qimin Zhan, Mi Deng, Jiye Zhu, Zemin Zhang, Ning Zhang.
      The heterogeneity of the tumour immune microenvironment (TIME), organized by various immune and stromal cells, is a major contributing factor of tumour metastasis, relapse and drug resistance1-3, but how different TIME subtypes are connected to the clinical relevance in liver cancer remains unclear. Here we performed single-cell RNA-sequencing (scRNA-seq) analysis of 189 samples collected from 124 patients and 8 mice with liver cancer. With more than 1 million cells analysed, we stratified patients into five TIME subtypes, including immune activation, immune suppression mediated by myeloid or stromal cells, immune exclusion and immune residence phenotypes. Different TIME subtypes were spatially organized and associated with chemokine networks and genomic features. Notably, tumour-associated neutrophil (TAN) populations enriched in the myeloid-cell-enriched subtype were associated with an unfavourable prognosis. Through in vitro induction of TANs and ex vivo analyses of patient TANs, we showed that CCL4+ TANs can recruit macrophages and that PD-L1+ TANs can suppress T cell cytotoxicity. Furthermore, scRNA-seq analysis of mouse neutrophil subsets revealed that they are largely conserved with those of humans. In vivo neutrophil depletion in mouse models attenuated tumour progression, confirming the pro-tumour phenotypes of TANs. With this detailed cellular heterogeneity landscape of liver cancer, our study illustrates diverse TIME subtypes, highlights immunosuppressive functions of TANs and sheds light on potential immunotherapies targeting TANs.
    DOI:  https://doi.org/10.1038/s41586-022-05400-x
  30. Sci Adv. 2022 Nov 11. 8(45): eabo1461
    Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry.
    Mingxi Yao, Ajay Tijore, Delfine Cheng, Jinyuan Vero Li, Anushya Hariharan, Boris Martinac, Guy Tran Van Nhieu, Charles D Cox, Michael Sheetz.
      Mechanosensing is an integral part of many physiological processes including stem cell differentiation, fibrosis, and cancer progression. Two major mechanosensing systems-focal adhesions and mechanosensitive ion channels-can convert mechanical features of the microenvironment into biochemical signals. We report here unexpectedly that the mechanosensitive calcium-permeable channel Piezo1, previously perceived to be diffusive on plasma membranes, binds to matrix adhesions in a force-dependent manner, promoting cell spreading, adhesion dynamics, and calcium entry in normal but not in most cancer cells tested except some glioblastoma lines. A linker domain in Piezo1 is needed for binding to adhesions, and overexpression of the domain blocks Piezo1 binding to adhesions, decreasing adhesion size and cell spread area. Thus, we suggest that Piezo1 is a previously unidentified component of focal adhesions in nontransformed cells that catalyzes adhesion maturation and growth through force-dependent calcium signaling, but this function is absent in most cancer cells.
    DOI:  https://doi.org/10.1126/sciadv.abo1461
  31. Curr Oncol. 2022 Oct 28. 29(11): 8146-8159
    Nomogram for Predicting Distant Metastasis of Pancreatic Ductal Adenocarcinoma: A SEER-Based Population Study.
    Weibo Li, Wei Wang, Lichao Yao, Zhigang Tang, Lulu Zhai.
      (1) Background: The aim of this study was to identify risk factors for distant metastasis of pancreatic ductal adenocarcinoma (PDAC) and develop a valid predictive model to guide clinical practice; (2) Methods: We screened 14328 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Lasso regression analysis combined with logistic regression analysis were used to determine the independent risk factors for PDAC with distant metastasis. A nomogram predicting the risk of distant metastasis in PDAC was constructed. A receiver operating characteristic (ROC) curve and consistency-index (C-index) were used to determine the accuracy and discriminate ability of the nomogram. A calibration curve was used to assess the agreement between the predicted probability of the model and the actual probability. Additionally, decision curve analysis (DCA) and clinical influence curve were employed to assess the clinical utility of the nomogram; (3) Results: Multivariate logistic regression analysis revealed that risk factors for distant metastasis of PDAC included age, primary site, histological grade, and lymph node status. A nomogram was successfully constructed, with an area under the curve (AUC) of 0.871 for ROC and a C-index of 0.871 (95% CI: 0.860-0.882). The calibration curve showed that the predicted probability of the model was in high agreement with the actual predicted probability. The DCA and clinical influence curve showed that the model had great potential clinical utility; (4) Conclusions: The risk model established in this study has a good predictive performance and a promising potential application, which can provide personalized clinical decisions for future clinical work.
    Keywords:  distant metastasis; pancreatic cancer; pancreatic ductal adenocarcinoma; prognosis; risk
    DOI:  https://doi.org/10.3390/curroncol29110643
  32. Biochem J. 2022 Nov 11. 479(21): 2311-2325
    PI(4,5)P2: signaling the plasma membrane.
    Rachel C Wills, Gerald R V Hammond.
      In the almost 70 years since the first hints of its existence, the phosphoinositide, phosphatidyl-D-myo-inositol 4,5-bisphosphate has been found to be central in the biological regulation of plasma membrane (PM) function. Here, we provide an overview of the signaling, transport and structural roles the lipid plays at the cell surface in animal cells. These include being substrate for second messenger generation, direct modulation of receptors, control of membrane traffic, regulation of ion channels and transporters, and modulation of the cytoskeleton and cell polarity. We conclude by re-evaluating PI(4,5)P2's designation as a signaling molecule, instead proposing a cofactor role, enabling PM-selective function for many proteins.
    Keywords:  5P2; PIP2; PtdIns4; lipid rafts; phospholipids; signaling
    DOI:  https://doi.org/10.1042/BCJ20220445
  33. Cell Metab. 2022 Nov 02. pii: S1550-4131(22)00461-2. [Epub ahead of print]
    Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
    Zaili Yang, Yazhen Huo, Shixin Zhou, Jingya Guo, Xiaotu Ma, Tao Li, Congli Fan, Likun Wang.
      A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.
    Keywords:  ER stress; HMGCR; IRE1α; MDSC; XBP1; cancer immunosuppression; cholesterol; macropinocytosis; small extracellular vesicle; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.010
  34. Phys Biol. 2022 Nov 07.
    Proteolytic and mechanical remodeling of the extracellular matrix by invadopodia in cancer.
    Louisane Perrin, Bojana Gligorijevic.
      Cancer invasion and metastasis require remodeling of the adjacent extracellular matrix (ECM). In this mini review, we will cover the mechanisms of proteolytic degradation and the mechanical remodeling of the ECM by cancer cells, with a focus on invadopodia. Invadopodia are membrane protrusions unique to cancer cells, characterized by an actin core and by the focal degradation of ECM via MMPs. While ECM can also be remodeled, at lower levels, by focal adhesions, or internal collagen digestion, invadopodia are now recognized as the major mechanism for MMP-dependent pericellular ECM degradation by cancer cells. Recent evidence suggests that the completion of epithelial-mesenchymal transition (EMT) may be dispensable for invadopodia and metastasis, and that invadopodia is required not only for mesenchymal, single cell invasion, but also for collective invasion. During collective invasion, invadopodia was then shown to be located in leader cells, allowing follower cells to move via cooperation. Collectively, this suggests that invadopodia function may be a requirement not only for later steps of metastasis, but also for early invasion of epithelial cells into the stromal tissue. Over the last decade, invadopodia studies have transitioned into in 3D and in vivo settings, leading to the confirmation of their essential role in metastasis in preclinical animal models. In summary, invadopodia may hold a great potential for individual risk assessment as a prognostic marker for metastasis, as well as therapeutic target.
    Keywords:  Epithelial-Mesenchymal Transition; Extracellular Matrix; Invadopodia; collective invasion; leader cells; mechanical remodeling; metastasis
    DOI:  https://doi.org/10.1088/1478-3975/aca0d8
  35. Nat Commun. 2022 Nov 11. 13(1): 6830
    Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.
    Kan Xie, Helmut Fuchs, Enzo Scifo, Dan Liu, Ahmad Aziz, Juan Antonio Aguilar-Pimentel, Oana Veronica Amarie, Lore Becker, Patricia da Silva-Buttkus, Julia Calzada-Wack, Yi-Li Cho, Yushuang Deng, A Cole Edwards, Lillian Garrett, Christina Georgopoulou, Raffaele Gerlini, Sabine M Hölter, Tanja Klein-Rodewald, Michael Kramer, Stefanie Leuchtenberger, Dimitra Lountzi, Phillip Mayer-Kuckuk, Lena L Nover, Manuela A Oestereicher, Clemens Overkott, Brandon L Pearson, Birgit Rathkolb, Jan Rozman, Jenny Russ, Kristina Schaaf, Nadine Spielmann, Adrián Sanz-Moreno, Claudia Stoeger, Irina Treise, Daniele Bano, Dirk H Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Beverly A Mock, Paolo Salomoni, Carsten Schmidt-Weber, Marco Weiergräber, Eckhard Wolf, Wolfgang Wurst, Valérie Gailus-Durner, Monique M B Breteler, Martin Hrabě de Angelis, Dan Ehninger.
      Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.
    DOI:  https://doi.org/10.1038/s41467-022-34515-y
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