bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒10‒02
28 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. The Interplay Among Pancreatic Cancer, Cachexia, Body Composition, and Diabetes.
  2. Transient Systemic Autophagy Inhibition is Selectively and Irreversibly Deleterious to Lung Cancer.
  3. GOT2 consider the tumor microenvironment.
  4. The role of RAS oncogenes in controlling epithelial mechanics.
  5. Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene.
  6. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity.
  7. Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
  8. Single cell metabolism: current and future trends.
  9. Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules.
  10. Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage.
  11. Multispectral confocal 3D imaging of intact healthy and tumor tissue using mLSR-3D.
  12. RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
  13. The NALCN channel regulates metastasis and nonmalignant cell dissemination.
  14. Upregulation of PD-L1 in Senescence and Aging.
  15. Cell competition in development, homeostasis and cancer.
  16. Organization, dynamics and mechanoregulation of integrin-mediated cell-ECM adhesions.
  17. An LKB1-mitochondria axis controls TH17 effector function.
  18. Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
  19. Rethinking cancer targeting strategies in the era of smart cell therapeutics.
  20. Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.
  21. The molecular architecture of cell cycle arrest.
  22. Modeling preclinical cancer studies under physioxia to enhance clinical translation.
  23. The importance of ancestry to understanding tumor mutation burden in cancer.
  24. A preponderance of gastrointestinal cancer patients transition into cachexia syndrome.
  25. TurnoveR: A Skyline External Tool for Analysis of Protein Turnover in Metabolic Labeling Studies.
  26. Interleukin-37 protects against acinar cell pyroptosis in acute pancreatitis.
  27. Extracellular vesicles as central regulators of blood vessel function in cancer.
  28. BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.
  1. Hematol Oncol Clin North Am. 2022 Sep 22. pii: S0889-8588(22)00069-7. [Epub ahead of print]
    The Interplay Among Pancreatic Cancer, Cachexia, Body Composition, and Diabetes.
    Richard F Dunne, Eric J Roeland.
      Pancreatic ductal adenocarcinoma (PDAC) is associated with complex changes in body composition. Visceral obesity and type 2 diabetes mellitus are established risk factors for developing PDAC; however, clinical and metabolic features of PDAC commonly lead to cancer cachexia, a hypermetabolic syndrome characterized by weight loss secondary to muscle and adipose tissue wasting. Reduction in muscle mass in patients with PDAC is associated with poorer survival in patients undergoing surgical resection and increased chemotherapy toxicity. Although no standardized treatment exists, a multidisciplinary, tailored, symptom-based approach is recommended to improve outcomes and quality of life for patients with PDAC and cachexia.
    Keywords:  Adiposity; Cachexia; Diabetes; Muscle; Pancreatic cancer; Weight loss
    DOI:  https://doi.org/10.1016/j.hoc.2022.07.001
  2. Cancer Res. 2022 Sep 26. pii: CAN-22-1039. [Epub ahead of print]
    Transient Systemic Autophagy Inhibition is Selectively and Irreversibly Deleterious to Lung Cancer.
    Khoosheh Khayati, Vrushank Bhatt, Taijin Lan, Fawzi Alogaili, Wenping Wang, Enrique Lopez, Zhixian Sherrie Hu, Samantha Gokhale, Liam Cassidy, Masashi Narita, Ping Xie, Eileen White, Jessie Yanxiang Guo.
      Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1039
  3. Trends Cancer. 2022 Sep 21. pii: S2405-8033(22)00195-9. [Epub ahead of print]
    GOT2 consider the tumor microenvironment.
    Brian T Do, Matthew G Vander Heiden.
      To thrive in a hypoxic and nutrient-limited tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells rewire their metabolism. Understanding PDAC cell metabolism may uncover vulnerabilities that can be targeted for improved therapy. Three recent studies find that the PDAC tumor microenvironment modulates the functional consequences of depleting the mitochondrially localized aspartate transaminase GOT2, thus providing new insights into the metabolism of this lethal cancer.
    DOI:  https://doi.org/10.1016/j.trecan.2022.09.004
  4. Trends Cell Biol. 2022 Sep 26. pii: S0962-8924(22)00212-4. [Epub ahead of print]
    The role of RAS oncogenes in controlling epithelial mechanics.
    Agata Nyga, Sushila Ganguli, Helen K Matthews, Buzz Baum.
      Mutations in RAS are key oncogenic drivers and therapeutic targets. Oncogenic Ras proteins activate a network of downstream signalling pathways, including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K), promoting cell proliferation and survival. However, there is increasing evidence that RAS oncogenes also alter the mechanical properties of both individual malignant cells and transformed tissues. Here we discuss the role of oncogenic RAS in controlling mechanical cell phenotypes and how these mechanical changes promote oncogenic transformation in single cells and tissues. RAS activation alters actin organisation and actomyosin contractility. These changes alter cell rheology and impact mechanosensing through changes in substrate adhesion and YAP/TAZ-dependent mechanotransduction. We then discuss how these changes play out in cell collectives and epithelial tissues by driving large-scale tissue deformations and the expansion of malignant cells. Uncovering how RAS oncogenes alter cell mechanics will lead to a better understanding of the morphogenetic processes that underlie tumour formation in RAS-mutant cancers.
    Keywords:  RAS; YAP/TAZ signalling; actin; epithelia; mechanobiology; mechanotransduction; myosin; oncogene; tissue mechanics
    DOI:  https://doi.org/10.1016/j.tcb.2022.09.002
  5. Front Cell Dev Biol. 2022 ;10 960341
    Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene.
    Michele Ferrara, Maria Samaden, Elena Ruggieri, Emilie Vénéreau.
      Cachexia is a devastating syndrome associated with the end-stage of several diseases, including cancer, and characterized by body weight loss and severe muscle and adipose tissue wasting. Although different cancer types are affected to diverse extents by cachexia, about 80% of all cancer patients experience this comorbidity, which highly reduces quality of life and response to therapy, and worsens prognosis, accounting for more than 25% of all cancer deaths. Cachexia represents an urgent medical need because, despite several molecular mechanisms have been identified, no effective therapy is currently available for this devastating syndrome. Most studies focus on skeletal muscle, which is indeed the main affected and clinically relevant organ, but cancer cachexia is characterized by a multiorgan failure. In this review, we focus on the current knowledge on the multiple tissues affected by cachexia and on the biomarkers with the attempt to define a chronological pathway, which might be useful for the early identification of patients who will undergo cachexia. Indeed, it is likely that the inefficiency of current therapies might be attributed, at least in part, to their administration in patients at the late stages of cachexia.
    Keywords:  adipose tissue; brain; cancer cachexia; gut; immune system; liver; pancreas; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2022.960341
  6. Nature. 2022 Sep 28.
    LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity.
    Akshay T Krishnamurty, Justin A Shyer, Minh Thai, Vineela Gandham, Matthew B Buechler, Yeqing Angela Yang, Rachana N Pradhan, Amber W Wang, Patricia L Sanchez, Yan Qu, Beatrice Breart, Cécile Chalouni, Debra Dunlap, James Ziai, Justin Elstrott, Neelie Zacharias, Weiguang Mao, Rebecca K Rowntree, Jack Sadowsky, Gail D Lewis, Thomas H Pillow, Barzin Y Nabet, Romain Banchereau, Lucinda Tam, Roger Caothien, Natasha Bacarro, Merone Roose-Girma, Zora Modrusan, Sanjeev Mariathasan, Sören Müller, Shannon J Turley.
      Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1-3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-022-05272-1
  7. Nat Commun. 2022 Sep 27. 13(1): 5671
    Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
    Xu Zhang, Vesselina M Pearsall, Chase M Carver, Elizabeth J Atkinson, Benjamin D S Clarkson, Ethan M Grund, Michelle Baez-Faria, Kevin D Pavelko, Jennifer M Kachergus, Thomas A White, Renee K Johnson, Courtney S Malo, Alan M Gonzalez-Suarez, Katayoun Ayasoufi, Kurt O Johnson, Zachariah P Tritz, Cori E Fain, Roman H Khadka, Mikolaj Ogrodnik, Diana Jurk, Yi Zhu, Tamara Tchkonia, Alexander Revzin, James L Kirkland, Aaron J Johnson, Charles L Howe, E Aubrey Thompson, Nathan K LeBrasseur, Marissa J Schafer.
      Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.
    DOI:  https://doi.org/10.1038/s41467-022-33226-8
  8. Metabolomics. 2022 Oct 01. 18(10): 77
    Single cell metabolism: current and future trends.
    Ahmed Ali, Shawn Davidson, Ernest Fraenkel, Ian Gilmore, Thomas Hankemeier, Jennifer A Kirwan, Andrew N Lane, Ingela Lanekoff, Mioara Larion, Laura-Isobel McCall, Michael Murphy, Jonathan V Sweedler, Caigang Zhu.
      Single cell metabolomics is an emerging and rapidly developing field that complements developments in single cell analysis by genomics and proteomics. Major goals include mapping and quantifying the metabolome in sufficient detail to provide useful information about cellular function in highly heterogeneous systems such as tissue, ultimately with spatial resolution at the individual cell level. The chemical diversity and dynamic range of metabolites poses particular challenges for detection, identification and quantification. In this review we discuss both significant technical issues of measurement and interpretation, and progress toward addressing them, with recent examples from diverse biological systems. We provide a framework for further directions aimed at improving workflow and robustness so that such analyses may become commonly applied, especially in combination with metabolic imaging and single cell transcriptomics and proteomics.
    Keywords:  Metabolic imaging; Single cell metabolism; Spatial metabolomics
    DOI:  https://doi.org/10.1007/s11306-022-01934-3
  9. J Cell Biol. 2022 Dec 05. pii: e202206132. [Epub ahead of print]221(12):
    Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules.
    Anup Parchure, Meng Tian, Danièle Stalder, Cierra K Boyer, Shelby C Bearrows, Kristen E Rohli, Jianchao Zhang, Felix Rivera-Molina, Bulat R Ramazanov, Sushil K Mahata, Yanzhuang Wang, Samuel B Stephens, David C Gershlick, Julia von Blume.
      Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). SGs fuse with the plasma membrane in response to a stimulus and deliver insulin to the bloodstream. The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. No cargo receptor for proinsulin has been identified. Here, we show that chromogranin (CG) proteins undergo liquid-liquid phase separation (LLPS) at a mildly acidic pH in the lumen of the TGN, and recruit clients like proinsulin to the condensates. Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. We propose that the TGN provides the milieu for converting CGs into a "cargo sponge" leading to partitioning of client molecules, thus facilitating receptor-independent client sorting. These findings provide a new receptor-independent sorting model in β-cells and many other cell types and therefore represent an innovation in the field of membrane trafficking.
    DOI:  https://doi.org/10.1083/jcb.202206132
  10. J Cell Biol. 2022 Nov 07. pii: e202207091. [Epub ahead of print]221(11):
    Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage.
    Jingyue Jia, Fulong Wang, Zambarlal Bhujabal, Ryan Peters, Michal Mudd, Thabata Duque, Lee Allers, Ruheena Javed, Michelle Salemi, Christian Behrends, Brett Phinney, Terje Johansen, Vojo Deretic.
      We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator-RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.
    DOI:  https://doi.org/10.1083/jcb.202207091
  11. Nat Protoc. 2022 Sep 30.
    Multispectral confocal 3D imaging of intact healthy and tumor tissue using mLSR-3D.
    Ravian L van Ineveld, Raphaël Collot, Mario Barrera Román, Anna Pagliaro, Nils Bessler, Hendrikus C R Ariese, Michiel Kleinnijenhuis, Marcel Kool, Maria Alieva, Susana M Chuva de Sousa Lopes, Ellen J Wehrens, Anne C Rios.
      Revealing the 3D composition of intact tissue specimens is essential for understanding cell and organ biology in health and disease. State-of-the-art 3D microscopy techniques aim to capture tissue volumes on an ever-increasing scale, while also retaining sufficient resolution for single-cell analysis. Furthermore, spatial profiling through multi-marker imaging is fast developing, providing more context and better distinction between cell types. Following these lines of technological advance, we here present a protocol based on FUnGI (fructose, urea and glycerol clearing solution for imaging) optical clearing of tissue before multispectral large-scale single-cell resolution 3D (mLSR-3D) imaging, which implements 'on-the-fly' linear unmixing of up to eight fluorophores during a single acquisition. Our protocol removes the need for repetitive illumination, thereby allowing larger volumes to be scanned with better image quality in less time, also reducing photo-bleaching and file size. To aid in the design of multiplex antibody panels, we provide a fast and manageable intensity equalization assay with automated analysis to design a combination of markers with balanced intensities suitable for mLSR-3D. We demonstrate effective mLSR-3D imaging of various tissues, including patient-derived organoids and xenografted tumors, and, furthermore, describe an optimized workflow for mLSR-3D imaging of formalin-fixed paraffin-embedded samples. Finally, we provide essential steps for 3D image data processing, including shading correction that does not require pre-acquired shading references and 3D inhomogeneity correction to correct fluorescence artefacts often afflicting 3D datasets. Together, this provides a one-week protocol for eight-fluorescent-marker 3D visualization and exploration of intact tissue of various origins at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41596-022-00739-x
  12. Nat Commun. 2022 Sep 26. 13(1): 5632
    RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
    TRACERx consortium
      Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11/LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making.
    DOI:  https://doi.org/10.1038/s41467-022-33290-0
  13. Nat Genet. 2022 Sep 29.
    The NALCN channel regulates metastasis and nonmalignant cell dissemination.
    Eric P Rahrmann, David Shorthouse, Amir Jassim, Linda P Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory J Hannon, Radhika Iyer, Jay A Blundon, Filipe C Lourenço, Jonathan Kay, Rosalynn M Nazarian, Benjamin A Hall, Stanislav S Zakharenko, Douglas J Winton, Liqin Zhu, Richard J Gilbertson.
      We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice with gadolinium-a NALCN channel blocker-similarly increased CTCs and metastases. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium, and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for antimetastatic therapies.
    DOI:  https://doi.org/10.1038/s41588-022-01182-0
  14. Mol Cell Biol. 2022 Sep 26. e0017122
    Upregulation of PD-L1 in Senescence and Aging.
    Angelique Onorati, Aaron P Havas, Brian Lin, Jayaraj Rajagopal, Payel Sen, Peter D Adams, Zhixun Dou.
      Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.
    Keywords:  PD-L1; SASP; aging; senescence
    DOI:  https://doi.org/10.1128/mcb.00171-22
  15. Nat Rev Mol Cell Biol. 2022 Sep 29.
    Cell competition in development, homeostasis and cancer.
    Sanne M van Neerven, Louis Vermeulen.
      Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.
    DOI:  https://doi.org/10.1038/s41580-022-00538-y
  16. Nat Rev Mol Cell Biol. 2022 Sep 27.
    Organization, dynamics and mechanoregulation of integrin-mediated cell-ECM adhesions.
    Pakorn Kanchanawong, David A Calderwood.
      The ability of animal cells to sense, adhere to and remodel their local extracellular matrix (ECM) is central to control of cell shape, mechanical responsiveness, motility and signalling, and hence to development, tissue formation, wound healing and the immune response. Cell-ECM interactions occur at various specialized, multi-protein adhesion complexes that serve to physically link the ECM to the cytoskeleton and the intracellular signalling apparatus. This occurs predominantly via clustered transmembrane receptors of the integrin family. Here we review how the interplay of mechanical forces, biochemical signalling and molecular self-organization determines the composition, organization, mechanosensitivity and dynamics of these adhesions. Progress in the identification of core multi-protein modules within the adhesions and characterization of rearrangements of their components in response to force, together with advanced imaging approaches, has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions. Perturbations of adhesion contribute to a broad range of diseases and to age-related dysfunction, thus an improved understanding of their molecular nature may facilitate therapeutic intervention in these conditions.
    DOI:  https://doi.org/10.1038/s41580-022-00531-5
  17. Nature. 2022 Sep 28.
    An LKB1-mitochondria axis controls TH17 effector function.
    Francesc Baixauli, Klara Piletic, Daniel J Puleston, Matteo Villa, Cameron S Field, Lea J Flachsmann, Andrea Quintana, Nisha Rana, Joy Edwards-Hicks, Mai Matsushita, Michal A Stanczak, Katarzyna M Grzes, Agnieszka M Kabat, Mario Fabri, George Caputa, Beth Kelly, Mauro Corrado, Yaarub Musa, Katarzyna J Duda, Gerhard Mittler, David O'Sullivan, Hiromi Sesaki, Thomas Jenuwein, Joerg M Buescher, Edward J Pearce, David E Sanin, Erika L Pearce.
      CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
    DOI:  https://doi.org/10.1038/s41586-022-05264-1
  18. Science. 2022 Sep 30. 377(6614): 1519-1529
    Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
    Giulia Notarangelo, Jessica B Spinelli, Elizabeth M Perez, Gregory J Baker, Kiran Kurmi, Ilaria Elia, Sylwia A Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J Golby, Shakchhi Joshi, Heide F Baron, Jefte M Drijvers, Peter Georgiev, Alison E Ringel, Elma Zaganjor, Samuel K McBrayer, Peter K Sorger, Arlene H Sharpe, Kai W Wucherpfennig, Sandro Santagata, Nathalie Y R Agar, Mario L Suvà, Marcia C Haigis.
      Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.
    DOI:  https://doi.org/10.1126/science.abj5104
  19. Nat Rev Cancer. 2022 Sep 29.
    Rethinking cancer targeting strategies in the era of smart cell therapeutics.
    Greg M Allen, Wendell A Lim.
      In the past several decades, the development of cancer therapeutics has largely focused on precision targeting of single cancer-associated molecules. Despite great advances, such targeted therapies still show incomplete precision and the eventual development of resistance due to target heterogeneity or mutation. However, the recent development of cell-based therapies such as chimeric antigen receptor (CAR) T cells presents a revolutionary opportunity to reframe strategies for targeting cancers. Immune cells equipped with synthetic circuits are essentially living computers that can be programmed to recognize tumours based on multiple signals, including both tumour cell-intrinsic and microenvironmental. Moreover, cells can be programmed to launch broad but highly localized therapeutic responses that can limit the potential for escape while still maintaining high precision. Although these emerging smart cell engineering capabilities have yet to be fully implemented in the clinic, we argue here that they will become much more powerful when combined with machine learning analysis of genomic data, which can guide the design of therapeutic recognition programs that are the most discriminatory and actionable. The merging of cancer analytics and synthetic biology could lead to nuanced paradigms of tumour recognition, more akin to facial recognition, that have the ability to more effectively address the complex challenges of treating cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00505-x
  20. Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2210353119
    Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.
    Menglan He, Alvin C Y Kuk, Mei Ding, Cheen Fei Chin, Dwight L A Galam, Jie Min Nah, Bryan C Tan, Hui Li Yeo, Geok Lin Chua, Peter I Benke, Markus R Wenk, Lena Ho, Federico Torta, David L Silver.
      The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
    Keywords:  Mfsd2a; autophagy; lysosome; phospholipid; transporter
    DOI:  https://doi.org/10.1073/pnas.2210353119
  21. Mol Syst Biol. 2022 Sep;18(9): e11087
    The molecular architecture of cell cycle arrest.
    Wayne Stallaert, Sovanny R Taylor, Katarzyna M Kedziora, Colin D Taylor, Holly K Sobon, Catherine L Young, Juanita C Limas, Jonah Varblow Holloway, Martha S Johnson, Jeanette Gowen Cook, Jeremy E Purvis.
      The cellular decision governing the transition between proliferative and arrested states is crucial to the development and function of every tissue. While the molecular mechanisms that regulate the proliferative cell cycle are well established, we know comparatively little about what happens to cells as they diverge into cell cycle arrest. We performed hyperplexed imaging of 47 cell cycle effectors to obtain a map of the molecular architecture that governs cell cycle exit and progression into reversible ("quiescent") and irreversible ("senescent") arrest states. Using this map, we found multiple points of divergence from the proliferative cell cycle; identified stress-specific states of arrest; and resolved the molecular mechanisms governing these fate decisions, which we validated by single-cell, time-lapse imaging. Notably, we found that cells can exit into senescence from either G1 or G2; however, both subpopulations converge onto a single senescent state with a G1-like molecular signature. Cells can escape from this "irreversible" arrest state through the upregulation of G1 cyclins. This map provides a more comprehensive understanding of the overall organization of cell proliferation and arrest.
    Keywords:  cell cycle; proliferation; quiescence; senescence; single-cell
    DOI:  https://doi.org/10.15252/msb.202211087
  22. Cancer Res. 2022 Sep 28. pii: CAN-22-2311. [Epub ahead of print]
    Modeling preclinical cancer studies under physioxia to enhance clinical translation.
    Adedeji K Adebayo, Harikrishna Nakshatri.
      Oxygen (O2) plays a key role in cellular homeostasis. O2 levels are tightly regulated in vivo such that each tissue receives an optimal amount to maintain physiologic status. Physiologic O2 levels in various organs range between 2-9% in vivo, with the highest levels of 9% in the kidneys and the lowest of 0.5% in parts of the brain. This physiologic range of O2 tensions is disrupted in pathologic conditions such as cancer, where it can reach as low as 0.5%. Regardless of the state, O2 tension in vivo is maintained at significantly lower levels than ambient O2, which is approximately 21%. Yet, routine in vitro cellular manipulations are carried out in ambient air, regardless of whether or not they are eventually transferred to hypoxic conditions for subsequent studies. Even brief exposure of hematopoietic stem cells to ambient air can cause detrimental effects through a mechanism termed extraphysiologic oxygen shock/stress (EPHOSS), leading to reduced engraftment capabilities. Here, we provide an overview of the effects of ambient air exposure on stem and non-stem cell subtypes, with a focus on recent findings that reveal the impact of EPHOSS on cancer cells.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2311
  23. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00433-0. [Epub ahead of print]
    The importance of ancestry to understanding tumor mutation burden in cancer.
    Alexandra Snyder, Nicholas McGranahan.
      In the current issue of Cancer Cell, Nassar and colleagues find that in solid tumors, tumor-only sequencing leads to an overestimate of the biomarker tumor mutation burden (TMB), particularly in patients of African or Asian ancestry. Correction of the TMB estimate improves the correlation between TMB and response to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2022.09.004
  24. J Cachexia Sarcopenia Muscle. 2022 Sep 27.
    A preponderance of gastrointestinal cancer patients transition into cachexia syndrome.
    Linda Anne Gilmore, Santiago Olaechea, Brian W Gilmore, Bhavani S Gannavarapu, Christian M Alvarez, Chul Ahn, Puneeth Iyengar, Rodney E Infante.
      BACKGROUND: Cancer cachexia is frequently documented by self-reported, single time-point weight histories. This approach lacks the granularity needed to fully elucidate the progression of cachexia syndrome. This study aimed to longitudinally assess body weight changes pre- and post-cancer diagnosis in gastrointestinal (GI) cancer patients.METHODS: Body weights and relevant clinical data recorded in the electronic health record 12 months pre- and post-GI cancer (colorectal, gastroesophageal, hepatobiliary and pancreatic) diagnosis were extracted. Weight loss was categorized by the International Consensus Definition for cachexia.
    RESULTS: A total of 879 patients were included in the final cohort including patients diagnosed with colorectal (n = 317), hepatocellular (n = 185), biliary (n = 72), pancreatic (n = 186) or gastroesophageal (n = 119) cancer. Stage of disease was equally distributed. Patients without cachexia at diagnosis (n = 608) remained weight stable during the 12 months pre-diagnosis (+0.5 ± 0.5% body weight; P = 0.99). Patients with cachexia at diagnosis (n = 271) remained weight stable 6 to 12 months prior to diagnosis (+0.4 ± 0.8%; P > 0.9999) and lost 8.7 ± 0.6% (P < 0.0001) within the 6 months pre-diagnosis. Patients without cachexia at diagnosis lost more weight post-diagnosis (6.3 ± 0.6%) than patients with cachexia at diagnosis (4.7 ± 1.0%; P = 0.01). Pre-diagnosis weight trajectories did not differ between primary malignancies or stage of disease in patients without or with cachexia at diagnosis (all P ≥ 0.05). Post-diagnosis weight trajectories did differ by primary malignancy (P ≤ 0.0002) and stage (P < 0.0001). In both patients without and with cachexia at diagnosis, colorectal patients lost the least amount of weight post-diagnosis and gastroesophageal patients lost the most amount of weight post-diagnosis. Stage 4 patients without or with cachexia at diagnosis lost the most weight post-diagnosis (P ≤ 0.0003). Regardless of cachexia status at diagnosis, patients lost more weight when treated with systemic therapy (7.1 ± 0.7%; P < 0.0001; n = 419) or radiation therapy (8.4 ± 1.4%; P = 0.02; n = 116) compared to those who did not. Patients who did not have surgery lost more weight post-diagnosis (7.6 ± 1.1%; P < 0.0001; n = 355) compared to those who did have surgery. By 12 months post-diagnosis, 83% of the surviving GI cancer patients in this cohort had transitioned into cachexia syndrome.
    CONCLUSIONS: Significant weight loss in patients with GI cancer cachexia at diagnosis initiates at least 6 months prior to diagnosis, and most patients will transition into cachexia syndrome post-diagnosis, regardless of pre-diagnosis weight change and stage of disease. These findings punctuate the importance of weight surveillance in cancer detection and earlier palliative interventions post-diagnosis in the GI cancer patient population.
    Keywords:  colorectal cancer; gastroesophageal cancer; hepatobiliary cancer; pancreatic cancer; weight loss
    DOI:  https://doi.org/10.1002/jcsm.13086
  25. J Proteome Res. 2022 Sep 27.
    TurnoveR: A Skyline External Tool for Analysis of Protein Turnover in Metabolic Labeling Studies.
    Nathan Basisty, Nicholas Shulman, Cameron Wehrfritz, Alexandra N Marsh, Samah Shah, Jacob Rose, Scott Ebert, Matthew Miller, Dao-Fu Dai, Peter S Rabinovitch, Christopher M Adams, Michael J MacCoss, Brendan MacLean, Birgit Schilling.
      In spite of its central role in biology and disease, protein turnover is a largely understudied aspect of most proteomic studies due to the complexity of computational workflows that analyze in vivo turnover rates. To address this need, we developed a new computational tool, TurnoveR, to accurately calculate protein turnover rates from mass spectrometric analysis of metabolic labeling experiments in Skyline, a free and open-source proteomics software platform. TurnoveR is a straightforward graphical interface that enables seamless integration of protein turnover analysis into a traditional proteomics workflow in Skyline, allowing users to take advantage of the advanced and flexible data visualization and curation features built into the software. The computational pipeline of TurnoveR performs critical steps to determine protein turnover rates, including isotopologue demultiplexing, precursor-pool correction, statistical analysis, and generation of data reports and visualizations. This workflow is compatible with many mass spectrometric platforms and recapitulates turnover rates and differential changes in turnover rates between treatment groups calculated in previous studies. We expect that the addition of TurnoveR to the widely used Skyline proteomics software will facilitate wider utilization of protein turnover analysis in highly relevant biological models, including aging, neurodegeneration, and skeletal muscle atrophy.
    Keywords:  Skyline; aging; mass spectrometry; metabolic labeling; protein degradation; protein synthesis; protein turnover; proteostasis; quantitative proteomics; stable isotope labeling
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00173
  26. JCI Insight. 2022 Sep 27. pii: e161244. [Epub ahead of print]
    Interleukin-37 protects against acinar cell pyroptosis in acute pancreatitis.
    Nan Ma, Chenchen Yuan, Juanjuan Shi, Qingtian Zhu, Yang Liu, Xiaojie Ma, Baiqiang Li, Weijuan Gong, Jing Xue, Guotao Lu, Weiqin Li, Jieshou Li.
      Acute pancreatitis (AP) is a local and/or systemic inflammatory disease that starts with acinar cell injury and necrosis, which has no effective medical treatment and thus remains a life-threatening condition. Interleukin-37 (IL-37), a natural immunomodulator, has demonstrated an anti-inflammatory effect; however, the role of IL-37 in AP remains unknown. The serum IL-37 levels of 39 healthy controls and 94 AP patients were measured. Cholecystokinin was applied to induce pancreatic acinar cell injury in vitro. Classical experimental AP models, such as caerulein, L-arginine, and Taurocholic acid sodium salt were included in the in vivo study. A transgenic mouse model with the IL-37 gene and administration of recombinant IL-37 were used to further investigate the function of IL-37 in AP. Pancreas-specific GSDMD knockout mice were used to explore the protective mechanism of IL-37. Our results showed that serum IL-37 levels of human were negatively correlated with the severity of AP. Furthermore, transgenic IL-37 mice and supplementation with recombinant IL-37 could both protect against AP. Mechanistically, IL-37 was able to suppress pyroptosis of injured acinar cells, and specific depletion of GSDMD in the pancreas counteracted the protective effect of IL-37. Our study demonstrates that IL-37 protects against acinar cell pyroptosis in AP.
    Keywords:  Cytokines; Gastroenterology; Inflammation; Pharmacology
    DOI:  https://doi.org/10.1172/jci.insight.161244
  27. Sci Signal. 2022 Sep 27. 15(753): eaaz4742
    Extracellular vesicles as central regulators of blood vessel function in cancer.
    Fernanda G Kugeratski, Alice Santi, Sara Zanivan.
      Blood vessels deliver oxygen and nutrients that sustain tumor growth and enable the dissemination of cancer cells to distant sites and the recruitment of intratumoral immune cells. In addition, the structural and functional abnormalities of the tumor vasculature foster the development of an aggressive tumor microenvironment and impair the efficacy of existing cancer therapies. Extracellular vesicles (EVs) have emerged as major players of tumor progression, and a growing body of evidence has demonstrated that EVs derived from cancer cells trigger multiple responses in endothelial cells that alter blood vessel function in tumors. EV-mediated signaling in endothelial cells can occur through the transfer of functional cargos such as miRNAs, lncRNAs, cirRNAs, and proteins. Moreover, membrane-bound proteins in EVs can elicit receptor-mediated signaling in endothelial cells. Together, these mechanisms reprogram endothelial cells and contribute to the sustained exacerbated angiogenic signaling typical of tumors, which, in turn, influences cancer progression. Targeting these angiogenesis-promoting EV-dependent mechanisms may offer additional strategies to normalize tumor vasculature. Here, we discuss the current knowledge pertaining to the contribution of cancer cell-derived EVs in mechanisms regulating blood vessel functions in tumors. Moreover, we discuss the translational opportunities in targeting the dysfunctional tumor vasculature using EVs and highlight the open questions in the field of EV biology that can be addressed using mass spectrometry-based proteomics analysis.
    DOI:  https://doi.org/10.1126/scisignal.aaz4742
  28. J Exp Med. 2022 Dec 05. pii: e20211476. [Epub ahead of print]219(12):
    BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.
    Charlotte J Imianowski, Sarah K Whiteside, Teresa Lozano, Alexander C Evans, Jayme D Benson, Christina J F Courreges, Firas Sadiyah, Colleen M Lau, Nordin D Zandhuis, Francis M Grant, Martijn J Schuijs, Panagiota Vardaka, Paula Kuo, Elizabeth J Soilleux, Jie Yang, Joseph C Sun, Tomohiro Kurosaki, Klaus Okkenhaug, Timotheus Y F Halim, Rahul Roychoudhuri.
      Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.
    DOI:  https://doi.org/10.1084/jem.20211476
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