bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–07–23
24 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. How nearby nutrients shape tumor growth.
  2. Intrapancreatic fat, pancreatitis, and pancreatic cancer.
  3. Location, location: Understanding the Metastatic Microenvironment.
  4. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.
  5. Monitoring the Cell Cycle of Tumor Cells in Mouse Models of Human Cancer.
  6. Driving arginine catabolism to activate systemic autophagy.
  7. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
  8. Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer.
  9. RAS GTPases and Interleaflet Coupling in the Plasma Membrane.
  10. Spartin is a receptor for the autophagy of lipid droplets.
  11. Development of small fluorescent probes for the analysis of autophagy kinetics.
  12. Analysis of ATG4C function in vivo.
  13. In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.
  14. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
  15. Protocol for automated multivariate quantitative-image-based cytometry analysis by fluorescence microscopy of asynchronous adherent cells.
  16. Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.
  17. Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.
  18. Plasma membrane of focal adhesions has a high content of cholesterol and phosphatidylcholine with saturated acyl chains.
  19. KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.
  20. A conserved pressure-driven mechanism for regulating cytosolic osmolarity.
  21. More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome.
  22. Cell cycle dynamics control fluidity of the developing mouse neuroepithelium.
  23. P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium.
  24. Lipid droplets: a cellular organelle vital in cancer cells.
  1. Elife. 2023 07 17. pii: e89825. [Epub ahead of print]12
    How nearby nutrients shape tumor growth.
    Nada Kalaany.
      Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.
    Keywords:  amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.89825
  2. Cell Mol Life Sci. 2023 Jul 15. 80(8): 206
    Intrapancreatic fat, pancreatitis, and pancreatic cancer.
    Anna C Lilly, Igor Astsaturov, Erica A Golemis.
      Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.
    Keywords:  Cilia; Ductal cells; Lipids; PDAC; Pancreatic steatosis
    DOI:  https://doi.org/10.1007/s00018-023-04855-z
  3. Mol Oncol. 2023 Jul 20.
    Location, location: Understanding the Metastatic Microenvironment.
    Neta Erez.
      Mortality from cancer is almost exclusively a result of tumor metastasis. Since advanced metastatic cancers are incurable, understanding the biology of tumor metastasis is one of the most significant challenges in cancer research today. A large body of research had established the central role of the microenvironment in facilitating tumor growth. However, the role of the metastatic microenvironment in supporting the multistage process of metastasis is still largely unresolved. To thrive at the metastatic site, disseminated cancer cells must adapt to distinct organ-specific microenvironments that exert unique cellular and molecular interactions to oppose or support the growth of metastatic cancer cells. Understanding these intricate interactions is key to the development of effective therapeutic strategies that may prevent metastatic relapse.
    Keywords:  Metastasis; metastatic niche; microenvironment; organ-specific
    DOI:  https://doi.org/10.1002/1878-0261.13492
  4. Nat Commun. 2023 07 18. 14(1): 4317
    Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.
    Ana Babic, Michael H Rosenthal, Tilak K Sundaresan, Natalia Khalaf, Valerie Lee, Lauren K Brais, Maureen Loftus, Leah Caplan, Sarah Denning, Anamol Gurung, Joanna Harrod, Khoschy Schawkat, Chen Yuan, Qiao-Li Wang, Alice A Lee, Leah H Biller, Matthew B Yurgelun, Kimmie Ng, Jonathan A Nowak, Andrew J Aguirre, Sangeeta N Bhatia, Matthew G Vander Heiden, Stephen K Van Den Eeden, Bette J Caan, Brian M Wolpin.
      Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41467-023-40024-3
  5. Cold Spring Harb Perspect Med. 2023 Jul 17. pii: a041383. [Epub ahead of print]
    Monitoring the Cell Cycle of Tumor Cells in Mouse Models of Human Cancer.
    Taylar Hammond, Julien Sage.
      Cell division is obligatory to tumor growth. However, both cancer cells and noncancer cells in tumors can be found in distinct stages of the cell cycle, which may inform the growth potential of these tumors, their propensity to metastasize, and their response to therapy. Hence, it is of utmost importance to monitor the cell cycle of tumor cells. Here we discuss well-established methods and new genetic advances to track the cell cycle of tumor cells in mouse models of human cancer. We also review recent genetic studies investigating the role of the cell-cycle machinery in the growth of tumors in vivo, with a focus on the machinery regulating the G1/S transition of the cell cycle.
    DOI:  https://doi.org/10.1101/cshperspect.a041383
  6. Autophagy Rep. 2022 ;1(1): 65-69
    Driving arginine catabolism to activate systemic autophagy.
    Yiming Zhang, Brian N Finck, Brian J DeBosch.
      Macroautophagy/autophagy is a conserved cellular self-digestive mechanism to catabolize superfluous or damaged cellular components to maintain cell homeostasis. Impaired autophagy underlies multiple pathophysiological states, including aging, neurodegenerative, inflammatory, and metabolic diseases. Intermittent fasting and caloric restriction are effective means by which to activate autophagy, yet relatively few people can sustain such intensive interventions in real-world settings. Moreover, current pharmacotherapies do not yet fully exploit autophagic flux as a target mechanism. Here, we discuss recent work, which demonstrates that arginine catabolism is a tractable process to activate autophagy with utility to treat obesity and its complications. Hepatocyte-specific transgenic activation of arginine catabolism, or systemic administration of an anti-tumor pharmacotherapy, pegylated arginine deiminase, each promote energy expenditure and insulin sensitivity, and reduce dyslipidemia and hepatic steatosis in obese mice. These effects depend upon hepatocyte Fgf21, and whole-body Becn1 expression. The data suggest that hepatocyte and systemic arginine catabolism drive autophagy, and identify an index pharmacological agent to leverage this process.
    DOI:  https://doi.org/10.1080/27694127.2022.2040763
  7. Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]
    Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
    Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.
      Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
    Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
  8. Clin Cancer Res. 2023 Jul 18. pii: CCR-22-3930. [Epub ahead of print]
    Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer.
    Harshabad Singh, Rachel B Keller, Kevin S Kapner, Julien Dilly, Srivatsan Raghavan, Chen Yuan, Elizabeth F Cohen, Michael Tolstorukov, Elizabeth Andrews, Lauren K Brais, Annacarolina da Silva, Kimberly Perez, Douglas A Rubinson, Rishi Surana, Marios Giannakis, Kimmie Ng, Thomas E Clancy, Matthew B Yurgelun, Benjamin L Schlechter, Jeffrey W Clark, Geoffrey I Shapiro, Michael H Rosenthal, Jason L Hornick, Valentina Nardi, Yvonne Y Li, Hersh Gupta, Andrew D Cherniack, Matthew Meyerson, James M Cleary, Jonathan A Nowak, Brian M Wolpin, Andrew J Aguirre.
       PURPOSE: Approximately 8-10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents.
    EXPERIMENTAL DESIGN: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multi-gene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer.
    RESULTS: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the mitogen activated kinase (MAPK) pathway, including BRAF mutations and in-frame deletions and receptor-tyrosine kinase (RTK) fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers such as GNAS, MYC, PIK3CA and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid (PDO) models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (Median Age: 62.6 vs. 65.7 years , p = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases.
    CONCLUSIONS: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3930
  9. Cold Spring Harb Perspect Biol. 2023 Jul 18. pii: a041414. [Epub ahead of print]
    RAS GTPases and Interleaflet Coupling in the Plasma Membrane.
    Junchen Liu, Neha Arora, Yong Zhou.
      RAS genes are frequently mutated in cancer. The primary signaling compartment of wild-type and constitutively active oncogenic mutant RAS proteins is the inner leaflet of the plasma membrane (PM). Thus, a better understanding of the unique environment of the PM inner leaflet is important to shed further light on RAS function. Over the past few decades, an integrated approach of superresolution imaging, molecular dynamic simulations, and biophysical assays has yielded new insights into the capacity of RAS proteins to sort lipids with specific headgroups and acyl chains, to assemble signaling nanoclusters on the inner PM. RAS proteins also sense and respond to changes in components of the outer PM leaflet, including glycophosphatidylinositol-anchored proteins, sphingophospholipids, glycosphingolipids, and galectins, as well as cholesterol that translocates between the two leaflets. Such communication between the inner and outer leaflets of the PM, called interleaflet coupling, allows RAS to potentially integrate extracellular mechanical and electrostatic information with intracellular biochemical signaling events, and reciprocally allows mutant RAS-transformed tumor cells to modify tumor microenvironments. Here, we review RAS-lipid interactions and speculate on potential mechanisms that allow communication between the opposing leaflets of the PM.
    DOI:  https://doi.org/10.1101/cshperspect.a041414
  10. Nat Cell Biol. 2023 Jul 20.
    Spartin is a receptor for the autophagy of lipid droplets.
      
    DOI:  https://doi.org/10.1038/s41556-023-01201-0
  11. iScience. 2023 Jul 21. 26(7): 107218
    Development of small fluorescent probes for the analysis of autophagy kinetics.
    Hajime Tajima Sakurai, Hidefumi Iwashita, Satoko Arakawa, Alifu Yikelamu, Mizuki Kusaba, Satoshi Kofuji, Hiroshi Nishina, Munetaka Ishiyama, Yuichiro Ueno, Shigeomi Shimizu.
      Autophagy is a dynamic process that degrades subcellular constituents, and its activity is measured by autophagic flux. The tandem proteins RFP-GFP-LC3 and GFP-LC3-RFP-LC3ΔG, which enable the visualization of autophagic vacuoles of different stages by differences in their fluorescent color, are useful tools to monitor autophagic flux, but they require plasmid transfection. In this study, we hence aimed to develop a new method to monitor autophagic flux using small cell-permeable fluorescent probes. We previously developed two green-fluorescent probes, DALGreen and DAPGreen, which detect autolysosomes and multistep autophagic vacuoles, respectively. We here developed a red-fluorescent autophagic probe, named DAPRed, which recognizes various autophagic vacuoles. By the combinatorial use of these green- and red-fluorescent probes, we were able to readily detect autophagic flux. Furthermore, these probes were useful not only for the visualization of canonical autophagy but also for alternative autophagy. DAPRed was also applicable for the detection of autophagy in living organisms.
    Keywords:  Biological sciences tools; Biotechnology; Cell biology; Optical imaging
    DOI:  https://doi.org/10.1016/j.isci.2023.107218
  12. Autophagy. 2023 Jul 17. 1-22
    Analysis of ATG4C function in vivo.
    Isaac Tamargo-Gómez, Gemma G Martínez-García, María F Suárez, Pablo Mayoral, Gabriel Bretones, Aurora Astudillo, Jesús Prieto-Lloret, Christina Sveen, Antonio Fueyo, Nikolai Engedal, Carlos López-Otín, Guillermo Mariño.
       ABBREVIATIONS: ATG4 (autophagy related 4 cysteine peptidase); ATG4A (autophagy related 4A cysteine peptidase); ATG4B (autophagy related 4B cysteine peptidase); ATG4C (autophagy related 4C cysteine peptidase); ATG4D (autophagy related 4D cysteine peptidase); Atg8 (autophagy related 8); GABARAP (GABA type A receptor-associated protein); GABARAPL1(GABA type A receptor-associated protein like 1); GABARAPL2 (GABA type A receptor-associated protein like 2); MAP1LC3A/LC3A (microtubule associated protein 1 light chain 3 alpha); MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta); mATG8 (mammalian Atg8); PE (phosphatidylethanolamine); PS (phosphatydylserine); SQSTM1/p62 (sequestosome 1).
    Keywords:  Animal models; GABARAP; LC3; autophagy; fibrosarcoma; lymphocyte
    DOI:  https://doi.org/10.1080/15548627.2023.2234799
  13. J Cancer Res Clin Oncol. 2023 Jul 20.
    In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.
    M Knoblauch, T Ma, I Beirith, D Koch, F Hofmann, K Heinrich, U Aghamaliev, S Sirtl, C B Westphalen, H Nieß, M Reichert, M K Angele, I Regel, A V Bazhin, J Werner, M Ilmer, Bernhard W Renz.
       PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs).
    METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs.
    RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids.
    CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.
    Keywords:  Organoids; Pancreatic cancer; Pancreatic cancer organoids; Tumor-immune interaction
    DOI:  https://doi.org/10.1007/s00432-023-05100-7
  14. Nature. 2023 Jul 19.
    Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
    Yogesh Goyal, Gianna T Busch, Maalavika Pillai, Jingxin Li, Ryan H Boe, Emanuelle I Grody, Manoj Chelvanambi, Ian P Dardani, Benjamin Emert, Nicholas Bodkin, Jonas Braun, Dylan Fingerman, Amanpreet Kaur, Naveen Jain, Pavithran T Ravindran, Ian A Mellis, Karun Kiani, Gretchen M Alicea, Mitchell E Fane, Syeda Subia Ahmed, Haiyin Li, Yeqing Chen, Cedric Chai, Jessica Kaster, Russell G Witt, Rossana Lazcano, Davis R Ingram, Sarah B Johnson, Khalida Wani, Margaret C Dunagin, Alexander J Lazar, Ashani T Weeraratna, Jennifer A Wargo, Meenhard Herlyn, Arjun Raj.
      Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
    DOI:  https://doi.org/10.1038/s41586-023-06342-8
  15. STAR Protoc. 2023 Jul 13. pii: S2666-1667(23)00413-6. [Epub ahead of print]4(3): 102446
    Protocol for automated multivariate quantitative-image-based cytometry analysis by fluorescence microscopy of asynchronous adherent cells.
    Laetitia Besse, Typhaine Rumiac, Anne Reynaud-Angelin, Cédric Messaoudi, Marie-Noëlle Soler, Sarah A E Lambert, Vincent Pennaneach.
      Here, we present a protocol for multivariate quantitative-image-based cytometry (QIBC) analysis by fluorescence microscopy of asynchronous adherent cells. We describe steps for the preparation, treatment, and fixation of cells, sample staining, and imaging for QIBC. We then detail image analysis with our open source Fiji script developed for QIBC and present multiparametric data visualization. Our QIBC Fiji script integrates modern artificial-intelligence-based tools, applying deep learning, for robust automated nuclei segmentation with minimal user adjustments, a major asset for efficient QIBC analysis. For complete details on the use and execution of this protocol, please refer to Besse et al. (2023).1.
    Keywords:  Cell-based Assays; Microscopy; Signal Transduction
    DOI:  https://doi.org/10.1016/j.xpro.2023.102446
  16. J Clin Invest. 2023 Jul 18. pii: e171267. [Epub ahead of print]
    Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.
    Cheen Fei Chin, Dwight LA Galam, Liang Gao, Bryan C Tan, Bernice H Wong, Geok-Lin Chua, Randy Y J Loke, Yen Ching Lim, Markus R Wenk, Miao Shan Lim, Wei-Qiang Leow, George Bb Goh, Federico Torta, David L Silver.
      The liver has a high demand for phosphatidylcholine (PC) particularly in overnutrition where reduced phospholipid levels have been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter Mfsd2a as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust NASH-like phenotype within just two weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFA). Treating hepatocytes with LPC containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid DHA promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA containing LPCs drive both hepatic lipid droplet formation, suppress lipogenesis and sustain hepatic phospholipid pools--processes that are critical for protecting the liver from excess dietary fat.
    Keywords:  Hepatology; Homeostasis; Metabolism; Mouse models; Transport
    DOI:  https://doi.org/10.1172/JCI171267
  17. Nutrition. 2023 Jun 04. pii: S0899-9007(23)00143-0. [Epub ahead of print]114 112114
    Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.
    Junjie Wang, Shanjun Tan, Jiahao Xu, Shuhao Li, Mingyue Yan, Fan Yang, Qiuyue Huang, Zhige Zhang, Yanni Zhang, Jun Han, Hao Liu, Qiulin Zhuang, Qiulei Xi, Qingyang Meng, Guohao Wu.
       OBJECTIVE: The current tools for evaluating cancer cachexia are either too simple to reflect the far-reaching effects of cachexia or too complicated to be used in daily practice. This study aimed to develop a cancer cachexia staging index (CCSI) that is both practical and comprehensive.
    METHODS: Patients with gastrointestinal cancers were prospectively included in the study. Clinical data including weight change, body composition, systematic inflammation, nutrition, and function status were entered into regression models to determine the best variable combination as well as their respective cutoff values and score distribution in the CCSI. The CCSI's ability to predict outcomes and evaluate the consequences of cachexia for patients were then assessed.
    RESULTS: Clinical information and test results from 10 568 patients were used to develop a CCSI composed of subjective and objective measures. Subjective measures included body mass index-adjusted weight loss grade, rate of weight loss, inflammation (neutrophil-to-lymphocyte ratio and C-reactive protein level), and prealbumin level. Objective measures included appetite status and physical status. Patients were diagnosed and stratified by the total CCSI score into 3 subgroups: no cachexia, mild or moderate cachexia, and severe cachexia. The CCSI grades showed good survival discrimination and were independently predictive of survival in multivariate analysis. Compared with the traditional Fearon criteria for diagnosing cancer cachexia, the CCSI was more accurate in predicting postoperative complications (net reclassification index [NRI], 2.8%; 95% CI, 0.0104-0.0456%), death (NRI, 10.68%; 95% CI, 0.0429-0.1708%), recurrence (NRI, 3.71%; 95% CI, 0.0082-0.0685%), and overall survival (NRI, 8.5%; 95% CI, 0.0219-0.1533%). The CCSI also had better discriminative ability than Fearon criteria in discriminating nutritional status, body composition, and systematic inflammation in patients with or without cachexia. A more detailed evaluation of a randomly selected subgroup (n = 1566) showed that CCSI grades had good discrimination of appetite and food intake status, physical function and muscle strength, symptom burden, and quality of life.
    CONCLUSIONS: The CCSI is a comprehensive and practical evaluation tool for cancer cachexia. It can predict postoperative outcomes and survival. The CCSI stages showed good discrimination when evaluating patients with cancer in terms of nutritional status, physical function, systematic inflammation, body composition, symptom burden, and quality of life.
    Keywords:  Cancer cachexia; Classification; Diagnosis; Outcome
    DOI:  https://doi.org/10.1016/j.nut.2023.112114
  18. J Cell Sci. 2023 Jul 20. pii: jcs.260763. [Epub ahead of print]
    Plasma membrane of focal adhesions has a high content of cholesterol and phosphatidylcholine with saturated acyl chains.
    Hiroshi Tachibana, Kodai Minoura, Tomohiro Omachi, Kohjiro Nagao, Takafumi Ichikawa, Yasuhisa Kimura, Nozomu Kono, Yuta Shimanaka, Hiroyuki Arai, Kazumitsu Ueda, Noriyuki Kioka.
      Cellular functions, such as differentiation and migration, are regulated by the extracellular microenvironment, including the extracellular matrix (ECM). Cells adhere to ECM through focal adhesions (FAs) and sense the surrounding microenvironments. While FA proteins have been actively investigated, little is known about the lipids in the plasma membrane at FAs. In this study, we examine the lipid composition at FAs with imaging and biochemical approaches. Using a cholesterol specific probe D4 with total internal reflection fluorescence microscopy and super-resolution microscopy, we show an enrichment of cholesterol at FAs simultaneously with FA assembly. Furthermore, we establish a method to isolate the lipid from FA-rich fractions and biochemical quantification of the lipids reveals the higher content of cholesterol and phosphatidylcholine with saturated fatty acid chains in the lipids of the FA-rich fraction than in either plasma membrane fraction or the whole cell membrane. These results demonstrate that plasma membrane at FAs has a locally distinct lipid composition compared to the bulk plasma membrane.
    Keywords:  Cholesterol; Focal adhesion; Lipid composition; Lipid raft
    DOI:  https://doi.org/10.1242/jcs.260763
  19. Nature. 2023 Jul 19.
    KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.
    Nicholas H Juul, Jung-Ki Yoon, Marina C Martinez, Neha Rishi, Yana I Kazadaeva, Maurizio Morri, Norma F Neff, Winston L Trope, Joseph B Shrager, Rahul Sinha, Tushar J Desai.
      Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells1. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.
    DOI:  https://doi.org/10.1038/s41586-023-06324-w
  20. Curr Biol. 2023 Jul 17. pii: S0960-9822(23)00846-1. [Epub ahead of print]
    A conserved pressure-driven mechanism for regulating cytosolic osmolarity.
    Katrina B Velle, Rikki M Garner, Tatihana K Beckford, Makaela Weeda, Chunzi Liu, Andrew S Kennard, Marc Edwards, Lillian K Fritz-Laylin.
      Controlling intracellular osmolarity is essential to all cellular life. Cells that live in hypo-osmotic environments, such as freshwater, must constantly battle water influx to avoid swelling until they burst. Many eukaryotic cells use contractile vacuoles to collect excess water from the cytosol and pump it out of the cell. Although contractile vacuoles are essential to many species, including important pathogens, the mechanisms that control their dynamics remain unclear. To identify the basic principles governing contractile vacuole function, we investigate here the molecular mechanisms of two species with distinct vacuolar morphologies from different eukaryotic lineages: the discoban Naegleria gruberi and the amoebozoan slime mold Dictyostelium discoideum. Using quantitative cell biology, we find that although these species respond differently to osmotic challenges, they both use vacuolar-type proton pumps for filling contractile vacuoles and actin for osmoregulation, but not to power water expulsion. We also use analytical modeling to show that cytoplasmic pressure is sufficient to drive water out of contractile vacuoles in these species, similar to findings from the alveolate Paramecium multimicronucleatum. These analyses show that cytoplasmic pressure is sufficient to drive contractile vacuole emptying for a wide range of cellular pressures and vacuolar geometries. Because vacuolar-type proton-pump-dependent contractile vacuole filling and pressure-dependent emptying have now been validated in three eukaryotic lineages that diverged well over a billion years ago, we propose that this represents an ancient eukaryotic mechanism of osmoregulation.
    Keywords:  Dictyostelium; Naegleria; actin; contractile vacuole; cytoskeleton; evolutionary cell biology; osmoregulation; osmotic pressure
    DOI:  https://doi.org/10.1016/j.cub.2023.06.061
  21. Sci Adv. 2023 Jul 21. 9(29): eadf4163
    More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome.
    Christopher J Minteer, Kyra Thrush, John Gonzalez, Peter Niimi, Mariya Rozenblit, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Albert T Higgins-Chen, Erin Hofstatter, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E Levine.
      Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro and tested on clinical tissues. This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.
    DOI:  https://doi.org/10.1126/sciadv.adf4163
  22. Nat Phys. 2023 ;19(7): 1050-1058
    Cell cycle dynamics control fluidity of the developing mouse neuroepithelium.
    Laura Bocanegra-Moreno, Amrita Singh, Edouard Hannezo, Marcin Zagorski, Anna Kicheva.
      As developing tissues grow in size and undergo morphogenetic changes, their material properties may be altered. Such changes result from tension dynamics at cell contacts or cellular jamming. Yet, in many cases, the cellular mechanisms controlling the physical state of growing tissues are unclear. We found that at early developmental stages, the epithelium in the developing mouse spinal cord maintains both high junctional tension and high fluidity. This is achieved via a mechanism in which interkinetic nuclear movements generate cell area dynamics that drive extensive cell rearrangements. Over time, the cell proliferation rate declines, effectively solidifying the tissue. Thus, unlike well-studied jamming transitions, the solidification uncovered here resembles a glass transition that depends on the dynamical stresses generated by proliferation and differentiation. Our finding that the fluidity of developing epithelia is linked to interkinetic nuclear movements and the dynamics of growth is likely to be relevant to multiple developing tissues.
    Keywords:  Biological physics; Biophysics
    DOI:  https://doi.org/10.1038/s41567-023-01977-w
  23. Commun Biol. 2023 07 17. 6(1): 740
    P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium.
    Rizwan Ahmad, Balawant Kumar, Raju Lama Tamang, Geoffrey A Talmon, Punita Dhawan, Amar B Singh.
      Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to examine if an interplay between autophagy and claudin-2 protects from colitis and associated epithelial injury. Crypt culture and intestinal epithelial cells (IECs) are subjected to stress, including starvation or DSS, the chemical that induces colitis in-vivo. Autophagy flux, cell survival, co-immunoprecipitation, proximity ligation assay, and gene mutational studies are performed. These studies reveal that under colitis/stress conditions, claudin-2 undergoes polyubiquitination and P62/SQSTM1-assisted degradation through autophagy. Inhibiting autophagy-mediated claudin-2 degradation promotes cell death and thus suggest that claudin-2 degradation promotes autophagy flux to promote cell survival. Overall, these data inform for the previously undescribed role for claudin-2 in facilitating IECs survival under stress conditions, which can be harnessed for therapeutic advantages.
    DOI:  https://doi.org/10.1038/s42003-023-05116-2
  24. Cell Death Discov. 2023 Jul 20. 9(1): 254
    Lipid droplets: a cellular organelle vital in cancer cells.
    Yi Jin, Yanjie Tan, Jian Wu, Zhuqing Ren.
      Lipid droplets (LDs) are cellular organelles comprising a core of neutral lipids (glycerides, sterols) encased within a single phospholipid membrane, responsible for storing surplus lipids and furnishing cellular energy. LDs engage in lipid synthesis, catabolism, and transport processes by interacting with other organelles (e.g., endoplasmic reticulum, mitochondria), and they play critical roles in regulating cellular stress and immunity. Recent research has uncovered that an elevated number of LDs is a hallmark of cancer cells, attributable to their enhanced lipid uptake and synthesis capacity, with lipids stored as LDs. Depletion of LDs in cancer cells induces apoptosis, prompting the emergence of small molecule antitumor drugs targeting LDs or key factors (e.g., FASN, SCD1) within the lipid synthesis pathway. Advancements in LD isolation and artificial synthesis have demonstrated their potential applicability in antitumor research. LDs extracted from murine adipose tissue and incubated with lipophilic antitumor drugs yield drug-coated LDs, which promote apoptosis in cancer cells. Furthermore, LDs have been employed as biological lenses to augment the resolution of subcellular structures (microfilaments, microtubules), facilitating the observation of intricate structures within thicker cells, including cancer cells. This review delineates the functional and metabolic mechanisms of LDs in cancer cells and encapsulates recent progress in LD-centered antitumor research, offering novel insights for tumor diagnosis and treatment.
    DOI:  https://doi.org/10.1038/s41420-023-01493-z
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