bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2020‒07‒26
73 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
  2. Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes.
  3. Redox priming promotes Aurora A activation during mitosis.
  4. Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer.
  5. The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis.
  6. Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome.
  7. Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
  8. A generalizable data-driven multicellular model of pancreatic ductal adenocarcinoma.
  9. Depletion of Macrophages Improves Therapeutic Response to Gemcitabine in Murine Pancreas Cancer.
  10. Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.
  11. Phase separation drives decision making in cell division.
  12. Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.
  13. STEEP mediates STING ER exit and activation of signaling.
  14. Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.
  15. Self-Eating for Muscle Fitness: Autophagy in the Control of Energy Metabolism.
  16. Basal-like and classical cells coexist in pancreatic cancer revealed by single-cell analysis on biopsy-derived pancreatic cancer organoids from the classical subtype.
  17. Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism.
  18. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.
  19. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities.
  20. Molecular logic of mTORC1 signalling as a metabolic rheostat.
  21. Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.
  22. SPARC enables genetic manipulation of precise proportions of cells.
  23. Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.
  24. Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise.
  25. Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.
  26. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis.
  27. CALCOCO1 is a soluble reticulophagy receptor.
  28. Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma.
  29. Lactate: the ugly duckling of energy metabolism.
  30. Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation.
  31. Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.
  32. The activities of drug inactive ingredients on biological targets.
  33. Beth Cindy Levine (1960-2020).
  34. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma.
  35. Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.
  36. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma.
  37. H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients.
  38. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue.
  39. Control strategies in systemic metabolism.
  40. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism.
  41. NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.
  42. Molecular determinants of large cargo transport into the nucleus.
  43. Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1.
  44. A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue.
  45. Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3.
  46. Membrane budding is a major mechanism of in vivo platelet biogenesis.
  47. Lipid sponge droplets as programmable synthetic organelles.
  48. Exoplanet secondary atmosphere loss and revival.
  49. Autophagy in kidney homeostasis and disease.
  50. Ramping up the autophagy-lysosome system to cope with osmotic stress.
  51. Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.
  52. Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine.
  53. Mechanism for the effects of FGF21.
  54. A stress-free stress response.
  55. Role and therapeutic potential of dietary ketone bodies in lymph vessel growth.
  56. Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma.
  57. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function.
  58. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.
  59. Organotypic culture assays for murine and human primary and metastatic-site tumors.
  60. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.
  61. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss.
  62. Metabolites Regulate Cell Signaling and Growth via Covalent Modification of Proteins.
  63. Selenium detoxification is required for cancer-cell survival.
  64. Defining relative mutational difficulty to understand cancer formation.
  65. Metabolic signaling in T cells.
  66. Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine.
  67. Inter-organ cross-talk in metabolic syndrome.
  68. ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis.
  69. Phosphoprotein-based biomarkers as predictors for cancer therapy.
  70. Treatment of ErbB2 breast cancer by mitochondrial targeting.
  71. Metabolic terminology: what's in a name?
  72. Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition.
  73. The Influence of Gut and Tumor Microbiome on Pancreatic Cancer Outcomes.
  1. Cancer Cell. 2020 Jul 08. pii: S1535-6108(20)30316-0. [Epub ahead of print]
    Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
    Nemanja Despot Marjanovic, Matan Hofree, Jason E Chan, David Canner, Katherine Wu, Marianna Trakala, Griffin G Hartmann, Olivia Smith, Jonathan Kim, Kelly Victoria Evans, Anna Hudson, Orr Ashenberg, Caroline B M Porter, Alborz Bejnood, Ayshwarya Subramanian, Kenneth Pitter, Yan Yan, Toni Delroy, Devan R Phillips, Nisargbhai Shah, Ojasvi Chaudhary, Alexander Tsankov, Travis Hollmann, Natasha Rekhtman, Pierre P Massion, John T Poirier, Linas Mazutis, Ruifang Li, Joo-Hyeon Lee, Angelika Amon, Charles M Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela.
      Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
    Keywords:  cell state transition; lung cancer; plasticity; single-cell transcriptomics; tumor evolution; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.012
  2. Cancer Discov. 2020 Jul 23. pii: CD-20-0133. [Epub ahead of print]
    Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes.
    Koji Miyabayashi, Lindsey A Baker, Astrid Deschenes, Benno Traub, Giuseppina Caligiuri, Dennis Plenker, Brinda Alagesan, Pascal Belleau, Siran Li, Jude Kendall, Gun Ho Jang, Risa Karakida Kawaguchi, Tim D D Somerville, Herve Tiriac, Chang-Il Hwang, Richard A Burkhart, Nicholas J Roberts, Laura D Wood, Ralph H Hruban, Jesse Gillis, Alexander Krasnitz, Christopher R Vakoc, Michael Wigler, Faiyaz Notta, Steven Gallinger, Youngkyu Park, David A Tuveson.
      Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated, however the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the Ras pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane bound proteins which may represent potential candidates for therapeutic intervention in PDAC patients.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0133
  3. Sci Signal. 2020 Jul 21. pii: eabb6707. [Epub ahead of print]13(641):
    Redox priming promotes Aurora A activation during mitosis.
    Daniel C Lim, Vladimir Joukov, T Justin Rettenmaier, Akiko Kumagai, William G Dunphy, James A Wells, Michael B Yaffe.
      Cell cycle-dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family of kinases and their downstream targets are key components of the cellular machinery that ensures the proper execution of mitosis and the accurate segregation of chromosomes to daughter cells. In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes in the intracellular redox state during mitosis and provide insights into how novel small-molecule inhibitors may be developed to target specific subpopulations of Aurora A.
    DOI:  https://doi.org/10.1126/scisignal.abb6707
  4. Cancer Discov. 2020 Jul 20. pii: CD-19-1366. [Epub ahead of print]
    Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer.
    Adam Pennycuick, Vitor H Teixeira, Khalid AbdulJabbar, Shan E Ahmed Raza, Tom Lund, Ayse U Akarca, Rachel Rosenthal, Lukas Kalinke, Deepak P Chandrasekharan, Christodoulos P Pipinikas, Henry Lee-Six, Robert E Hynds, Kate H C Gowers, Jake Y Henry, Fraser R Millar, Yeman B Hagos, Celine Denais, Mary Falzon, David A Moore, Sophia Antoniou, Pascal F Durrenberger, Andrew J S Furness, Bernadette Carroll, Claire Marceaux, Marie-Liesse Asselin-Labat, William Larson, Courtney Betts, Lisa M Coussens, Ricky M Thakrar, Jeremy George, Charles Swanton, Christina Thirlwell, Peter J Campbell, Teresa Marafioti, Yinyin Yuan, Sergio A Quezada, Nicholas McGranahan, Sam M Janes.
      Before squamous cell lung cancer develops, pre-cancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. While recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of pre-cancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in-situ lesions harbour more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27/CCR10 signalling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the CIS lesions as the adjacent stroma of progressive and regressive lesions are transcriptomically similar.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1366
  5. Nat Metab. 2020 Jan;2(1): 62-80
    The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis.
    Vassilis Papalazarou, Tong Zhang, Nikki R Paul, Amelie Juin, Marco Cantini, Oliver D K Maddocks, Manuel Salmeron-Sanchez, Laura M Machesky.
      Pancreatic ductal adenocarcinoma is particularly metastatic, with dismal survival rates and few treatment options. Stiff fibrotic stroma is a hallmark of pancreatic tumours, but how stromal mechanosensing affects metastasis is still unclear. Here, we show that mechanical changes in the pancreatic cancer cell environment affect not only adhesion and migration, but also ATP/ADP and ATP/AMP ratios. Unbiased metabolomic analysis reveals that the creatine-phosphagen ATP-recycling system is a major mechanosensitive target. This system depends on arginine flux through the urea cycle, which is reflected by the increased incorporation of carbon and nitrogen from L-arginine into creatine and phosphocreatine on stiff matrix. We identify that CKB is a mechanosensitive transcriptional target of YAP, and thus it increases phosphocreatine production. We further demonstrate that the creatine-phosphagen system has a role in invasive migration, chemotaxis and liver metastasis of cancer cells.
    DOI:  https://doi.org/10.1038/s42255-019-0159-z
  6. Aging Cell. 2020 Jul 25.
    Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome.
    Xiaodong Mu, Chieh Tseng, William S Hambright, Polina Matre, Chih-Yi Lin, Palas Chanda, Wanqun Chen, Jianhua Gu, Sudheer Ravuri, Yan Cui, Ling Zhong, John P Cooke, Laura J Niedernhofer, Paul D Robbins, Johnny Huard.
      Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle-derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24-/- (Z24-/- ) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin-induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F-actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei-induced cGAS-Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24- / - mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.
    Keywords:  accelerated aging; cell nucleus; cellular senescence; skeletal muscle; stem cells
    DOI:  https://doi.org/10.1111/acel.13152
  7. Nat Metab. 2019 Jan;1(1): 133-146
    Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
    Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Fadila Benhamed, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Sam Virtue, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Sandra Guilmeau, Valentin Barquissau, Diane Beuzelin, Sophie Bonnel, Marie Marques, Boris Monge-Roffarello, Corinne Lefort, Barbara Fielding, Thierry Sulpice, Arne Astrup, Bernard Payrastre, Justine Bertrand-Michel, Emmanuelle Meugnier, Laetitia Ligat, Frédéric Lopez, Hervé Guillou, Charlotte Ling, Cecilia Holm, Remi Rabasa-Lhoret, Wim H M Saris, Vladimir Stich, Peter Arner, Mikael Rydén, Cedric Moro, Nathalie Viguerie, Matthew Harms, Stefan Hallén, Antonio Vidal-Puig, Hubert Vidal, Catherine Postic, Dominique Langin.
      Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
    Keywords:  ChREBP; ELOVL Fatty Acid Elongase 6; ELOVL6 Expression; Hormone-sensitive Lipase; Insulin Signaling
    DOI:  https://doi.org/10.1038/s42255-018-0007-6
  8. Gigascience. 2020 Jul 01. pii: giaa075. [Epub ahead of print]9(7):
    A generalizable data-driven multicellular model of pancreatic ductal adenocarcinoma.
    Boris Aguilar, David L Gibbs, David J Reiss, Mark McConnell, Samuel A Danziger, Andrew Dervan, Matthew Trotter, Douglas Bassett, Robert Hershberg, Alexander V Ratushny, Ilya Shmulevich.
      BACKGROUND: Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer.RESULTS: By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type-specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis.
    CONCLUSIONS: The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies.
    Keywords:  cancer modeling; data-driven model; multicellular model; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1093/gigascience/giaa075
  9. Cancers (Basel). 2020 Jul 20. pii: E1978. [Epub ahead of print]12(7):
    Depletion of Macrophages Improves Therapeutic Response to Gemcitabine in Murine Pancreas Cancer.
    Soeren M Buchholz, Robert G Goetze, Shiv K Singh, Christoph Ammer-Herrmenau, Frances M Richards, Duncan I Jodrell, Malte Buchholz, Patrick Michl, Volker Ellenrieder, Elisabeth Hessmann, Albrecht Neesse.
      BACKGROUND: The tumor microenvironment (TME) is composed of fibro-inflammatory cells and extracellular matrix (ECM) components. However, the exact contribution of the various TME compartments towards therapeutic response is unknown. Here, we aim to dissect the specific contribution of tumor-associated macrophages (TAMs) towards drug delivery and response in pancreatic ductal adenocarcinoma (PDAC).METHODS: The effect of gemcitabine was assessed in human and murine macrophages, human pancreatic stellate cells (hPSCs), and tumor cells (L3.6pl, BxPC3 and KPC) in vitro. The drug metabolism of gemcitabine was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Preclinical studies were conducted using KrasG12D;p48-Cre and KrasG12D;p53172H;Pdx-Cre mice to investigate gemcitabine delivery at different stages of tumor progression and upon pharmacological TAM depletion.
    RESULTS: Gemcitabine accumulation was significantly increased in murine PDAC tissue compared to pancreatic intraepithelial neoplasia (PanIN) lesions and healthy control pancreas tissue. In vitro, macrophages accumulated and rapidly metabolized gemcitabine resulting in a significant drug scavenging effect for gemcitabine. Finally, pharmacological TAM depletion enhanced therapeutic response to gemcitabine in tumor-bearing KPC mice.
    CONCLUSION: Macrophages rapidly metabolize gemcitabine in vitro, and pharmacological depletion improves the therapeutic response to gemcitabine in vivo. Our study supports the notion that TAMs might be a promising therapeutic target in PDAC.
    Keywords:  chemoresistance; drug delivery; macrophages; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers12071978
  10. Nat Metab. 2020 Jul 06.
    Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.
    Ziwen Zhu, Abhinav Achreja, Noah Meurs, Olamide Animasahun, Sarah Owen, Anjali Mittal, Pooja Parikh, Ting-Wen Lo, Janusz Franco-Barraza, Jiaqi Shi, Valerie Gunchick, Mara H Sherman, Edna Cukierman, Andrew M Pickering, Anirban Maitra, Vaibhav Sahai, Meredith A Morgan, Sunitha Nagrath, Theodore S Lawrence, Deepak Nagrath.
      Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.
    DOI:  https://doi.org/10.1038/s42255-020-0226-5
  11. J Biol Chem. 2020 07 22. pii: jbc.REV120.011746. [Epub ahead of print]
    Phase separation drives decision making in cell division.
    Xing Liu, Xu Liu, Haowei Wang, Zhen Dou, Ke Ruan, Donald L Hill, Lin Li, Yunyu Shi, Xuebiao Yao.
      Liquid-liquid phase separation (LLPS) of biomolecules drives the formation of subcellular compartments with distinct physicochemical properties. These compartments, free of lipid bilayers and therefore called membraneless organelles, include nucleoli, centrosomes, heterochromatin, and centromeres. These have emerged as a new paradigm to account for subcellular organization and cell fate decisions. Here we summarize recent studies linking LLPS to mitotic spindle, heterochromatin, and centromere assembly and their plasticity controls in the context of the cell division cycle, highlighting a functional role for phase behavior and material properties of proteins assembled onto heterochromatin, centromeres, and central spindles via LLPS. The techniques and tools for visualizing and harnessing membraneless organelle dynamics and plasticity in mitosis are also discussed, as is the potential for these discoveries to promote new research directions for investigating chromosome dynamics, plasticity, and inter-chromosome interactions in the decision-making process during mitosis.
    Keywords:  CENP-E; bubristatin; centromere; centrosome; chemical biology; chromatin; chromosomes; membraneless organelle; mitosis; mitotic spindle; molecular imaging; molecular motor; organoids; subcellular organelle; syntelin
    DOI:  https://doi.org/10.1074/jbc.REV120.011746
  12. Science. 2020 Jul 24. 369(6502): 397-403
    Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.
    Yi Xu, Yang Zhang, Juan C García-Cañaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian A Blair, Joshua D Rabinowitz, Xiaolu Yang.
      Embryonic stem cells can propagate indefinitely in a pluripotent state, able to differentiate into all types of specialized cells when restored to the embryo. What sustains their pluripotency during propagation remains unclear. Here, we show that core pluripotency factors OCT4 and SOX2 suppress chaperone-mediated autophagy (CMA), a selective form of autophagy, until the initiation of differentiation. Low CMA activity promotes embryonic stem cell self-renewal, whereas its up-regulation enhances differentiation. CMA degrades isocitrate dehydrogenases IDH1 and IDH2 and reduces levels of intracellular α-ketoglutarate, an obligatory cofactor for various histone and DNA demethylases involved in pluripotency. These findings suggest that CMA mediates the effect of core pluripotency factors on metabolism, shaping the epigenetic landscape of stem cells and governing the balance between self-renewal and differentiation.
    DOI:  https://doi.org/10.1126/science.abb4467
  13. Nat Immunol. 2020 Aug;21(8): 868-879
    STEEP mediates STING ER exit and activation of signaling.
    Bao-Cun Zhang, Ramya Nandakumar, Line S Reinert, Jinrong Huang, Anders Laustsen, Zong-Liang Gao, Cheng-Long Sun, Søren Beck Jensen, Anne Troldborg, Sonia Assil, Martin F Berthelsen, Carsten Scavenius, Yan Zhang, Samuel J Windross, David Olagnier, Thaneas Prabakaran, Chiranjeevi Bodda, Ryo Narita, Yujia Cai, Cong-Gang Zhang, Harald Stenmark, Christine M Doucet, Takeshi Noda, Zheng Guo, Raphaela Goldbach-Mansky, Rune Hartmann, Zhijian J Chen, Jan J Enghild, Rasmus O Bak, Martin K Thomsen, Søren R Paludan.
      STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.
    DOI:  https://doi.org/10.1038/s41590-020-0730-5
  14. FASEB J. 2020 Jul 21.
    Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.
    Xunhao Xiong, Geeta Rao, Ram Vinod Roy, Yushan Zhang, Nicolas Means, Anindya Dey, Martha Tsaliki, Sounik Saha, Sanjib Bhattacharyya, Shailendra Kumar Dhar Dwivedi, Chinthalapally V Rao, Daniel J McCormick, Danny Dhanasekaran, Kai Ding, Elizabeth Gillies, Min Zhang, Da Yang, Resham Bhattacharya, Priyabrata Mukherjee.
      Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.
    Keywords:  KRAS; UBAP2; macropinocytosis; pancreatic cancer; small GTPases; therapeutic target
    DOI:  https://doi.org/10.1096/fj.201902826RR
  15. Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30538-4. [Epub ahead of print]54(2): 268-281
    Self-Eating for Muscle Fitness: Autophagy in the Control of Energy Metabolism.
    David Sebastián, Antonio Zorzano.
      Cellular processes that sense and transmit metabolic changes are crucial for adaptation to external signals. In this regard, autophagy provides energy upon nutrient deprivation and represents a quality control mechanism that eliminates damaged organelles or proteins. Here, we review recent findings on the metabolic pathways controlling autophagy in skeletal muscle, a plastic tissue that undergoes major changes in energy demands. We also analyze the implications of autophagy in the regulation of energy metabolism in muscle and how alterations in this process affect energy homeostasis at the whole-body level and the development of metabolic diseases and aging.
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.030
  16. FASEB J. 2020 Jul 20.
    Basal-like and classical cells coexist in pancreatic cancer revealed by single-cell analysis on biopsy-derived pancreatic cancer organoids from the classical subtype.
    Natalia Juiz, Abdessamad Elkaoutari, Martin Bigonnet, Odile Gayet, Julie Roques, Rémy Nicolle, Juan Iovanna, Nelson Dusetti.
      Pancreatic ductal adenocarcinoma (PDAC) is composed of stromal, immune, and cancerous epithelial cells. Transcriptomic analysis of the epithelial compartment allows classification into different phenotypic subtypes as classical and basal-like. However, little is known about the intra-tumor heterogeneity particularly in the epithelial compartment. Growing evidences suggest that this phenotypic segregation is not so precise and different cancerous cell types may coexist in a single tumor. To test this hypothesis, we performed single-cell transcriptomic analyses using combinational barcoding exclusively on epithelial cells from six different classical PDAC patients obtained by Endoscopic Ultrasound (EUS) with Fine Needle Aspiration (FNA). To purify the epithelial compartment, PDAC were grown as biopsy-derived pancreatic cancer organoids. Single-cell transcriptomic analysis allowed the identification of four main cell clusters present in different proportions in all tumors. Remarkably, although all these tumors were classified as classical, one cluster present in all corresponded to a basal-like phenotype. These results reveal an unanticipated high heterogeneity of pancreatic cancers and demonstrate that basal-like cells, which have a highly aggressive phenotype, are more widespread than expected.
    Keywords:  combinational barcoding; intra-tumor heterogeneity; single-cell analysis; transcriptomics
    DOI:  https://doi.org/10.1096/fj.202000363RR
  17. Nat Metab. 2020 Jun;2(6): 487-498
    Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism.
    Erol C Bayraktar, Konnor La, Kara Karpman, Gokhan Unlu, Ceren Ozerdem, Dylan J Ritter, Hanan Alwaseem, Henrik Molina, Hans-Heinrich Hoffmann, Alec Millner, G Ekin Atilla-Gokcumen, Eric R Gamazon, Amy R Rushing, Ela W Knapik, Sumanta Basu, Kıvanç Birsoy.
      Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions1-3. Here, using the debiased sparse partial correlation (DSPC) method3, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways.
    DOI:  https://doi.org/10.1038/s42255-020-0206-9
  18. Nat Chem Biol. 2020 Jul 20.
    Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.
    Julia M D Grandjean, Aparajita Madhavan, Lauren Cech, Bryan O Seguinot, Ryan J Paxman, Emery Smith, Louis Scampavia, Evan T Powers, Christina B Cooley, Lars Plate, Timothy P Spicer, Jeffery W Kelly, R Luke Wiseman.
      Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
    DOI:  https://doi.org/10.1038/s41589-020-0584-z
  19. Nat Metab. 2020 Feb;2(2): 132-141
    Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities.
    Binlu Huang, Bao-Liang Song, Chenqi Xu.
      Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-derived metabolites play complex roles in supporting cancer progression and suppressing immune responses. Preclinical and clinical studies have shown that manipulating cholesterol metabolism inhibits tumour growth, reshapes the immunological landscape and reinvigorates anti-tumour immunity. Here, we review cholesterol metabolism in cancer cells, its role in cancer progression and the mechanisms through which cholesterol metabolites affect immune cells in the tumour microenvironment. We also discuss therapeutic strategies aimed at interfering with cholesterol metabolism, and how the combination of such approaches with existing anti-cancer therapies can have synergistic effects, thus offering new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s42255-020-0174-0
  20. Nat Metab. 2019 Mar;1(3): 321-333
    Molecular logic of mTORC1 signalling as a metabolic rheostat.
    Alexander J Valvezan, Brendan D Manning.
      The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) serves as a key conduit between growth signals and the metabolic processes underlying cell growth. The activation state of mTORC1 is controlled by intracellular nutrients and energy, as well as exogenous hormones and growth factors, thereby integrating local and systemic growth signals. Here we discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism. After activation, mTORC1 promotes the conversion of available nutrients and energy into the major macromolecular species contributing to cellular mass, including proteins, nucleic acids and lipids, while suppressing the autophagic recycling of these macromolecules back into their nutrient constituents. Given that uncoupling of mTORC1 from its normal regulatory inputs contributes to many diseases-including cancer, genetic tumour syndromes, metabolic diseases, autoimmune diseases and neurological disorders-understanding the molecular logic of the mTORC1 network and how to modulate it may present therapeutic opportunities for treatment of a broad range of diseases and potentially even for the extension of lifespan.
    DOI:  https://doi.org/10.1038/s42255-019-0038-7
  21. Nat Metab. 2019 Oct;1(10): 958-965
    Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.
    Riikka H Hämäläinen, Juan C Landoni, Kati J Ahlqvist, Steffi Goffart, Sanna Ryytty, M Obaidur Rahman, Virginia Brilhante, Katherine Icay, Sampsa Hautaniemi, Liya Wang, Marikki Laiho, Anu Suomalainen.
      Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.
    DOI:  https://doi.org/10.1038/s42255-019-0120-1
  22. Nat Neurosci. 2020 Jul 20.
    SPARC enables genetic manipulation of precise proportions of cells.
    Jesse Isaacman-Beck, Kristine C Paik, Carl F R Wienecke, Helen H Yang, Yvette E Fisher, Irving E Wang, Itzel G Ishida, Gaby Maimon, Rachel I Wilson, Thomas R Clandinin.
      Many experimental approaches rely on controlling gene expression in select subsets of cells within an individual animal. However, reproducibly targeting transgene expression to specific fractions of a genetically defined cell type is challenging. We developed Sparse Predictive Activity through Recombinase Competition (SPARC), a generalizable toolkit that can express any effector in precise proportions of post-mitotic cells in Drosophila. Using this approach, we demonstrate targeted expression of many effectors in several cell types and apply these tools to calcium imaging of individual neurons and optogenetic manipulation of sparse cell populations in vivo.
    DOI:  https://doi.org/10.1038/s41593-020-0668-9
  23. Aging Cell. 2020 Jul 21. e13195
    Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.
    Ji Sun Moon, Ludger J E Goeminne, Jung Tae Kim, Jing Wen Tian, Seok-Hwan Kim, Ha Thi Nga, Seul Gi Kang, Baeki E Kang, Jin-Seok Byun, Young-Sun Lee, Jae-Han Jeon, Minho Shong, Johan Auwerx, Dongryeol Ryu, Hyon-Seung Yi.
      Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.
    Keywords:  T cell; aging; inflammation; mitochondria; senescence
    DOI:  https://doi.org/10.1111/acel.13195
  24. Nat Metab. 2020 Jul 20.
    Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise.
    Tara L MacDonald, Pattarawan Pattamaprapanont, Prerana Pathak, Natalie Fernandez, Ellen C Freitas, Samar Hafida, Joanna Mitri, Steven L Britton, Lauren G Koch, Sarah J Lessard.
      Increased aerobic exercise capacity, as a result of exercise training, has important health benefits. However, some individuals are resistant to improvements in exercise capacity, probably due to undetermined genetic and environmental factors. Here, we show that exercise-induced improvements in aerobic capacity are blunted and aerobic remodelling of skeletal muscle is impaired in several animal models associated with chronic hyperglycaemia. Our data point to chronic hyperglycaemia as a potential negative regulator of aerobic adaptation, in part, via glucose-mediated modifications of the extracellular matrix, impaired vascularization and aberrant mechanical signalling in muscle. We also observe low exercise capacity and enhanced c-Jun N-terminal kinase activation in response to exercise in humans with impaired glucose tolerance. Our work indicates that current shifts in dietary and metabolic health, associated with increasing incidence of hyperglycaemia, might impair muscular and organismal adaptations to exercise training, including aerobic capacity as one of its key health outcomes.
    DOI:  https://doi.org/10.1038/s42255-020-0240-7
  25. Proc Natl Acad Sci U S A. 2020 Jul 20. pii: 202010682. [Epub ahead of print]
    Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.
    Michael N Trinh, Michael S Brown, Joseph L Goldstein, Jaeil Han, Gonçalo Vale, Jeffrey G McDonald, Joachim Seemann, Joshua T Mendell, Feiran Lu.
      Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.
    Keywords:  CRISPR screen; PTDSS1; cholesterol; phosphatidylserine; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2010682117
  26. Nat Metab. 2019 Jan;1(1): 147-157
    Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis.
    Xiao Zhao, Pamela Psarianos, Laleh Soltan Ghoraie, Kenneth Yip, David Goldstein, Ralph Gilbert, Ian Witterick, Hilary Pang, Ali Hussain, Ju Hee Lee, Justin Williams, Scott V Bratman, Laurie Ailles, Benjamin Haibe-Kains, Fei-Fei Liu.
      Extracellular matrix (ECM) homeostasis is essential for normal tissue function, and its disruption by iatrogenic injury, trauma, or disease results in fibrosis. Skin ECM homeostasis is maintained by a complex process that involves an integration of cytokine and environmental mediators. However, it is unclear, in both normal and disease states, how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. Here we show a consistent downregulation in fatty acid oxidation (FAO) and upregulation of glycolysis in fibrotic skin and in normal skin with abundant ECM. Perturbation of glycolysis and FAO pathway enzymes reveals their reciprocal effects in ECM upregulation and downregulation, respectively. Increasing peroxisome proliferator-activated receptor (PPAR) signalling, an inducer of the FAO pathway, generates a catabolic fibroblast phenotype characterised by inhibition of ECM transcription and enhanced ECM internalization and lysosomal degradation. In contrast, suppression of glycolysis inhibits ECM gene transcription and protein levels, independently of an intact FAO pathway or PPAR signalling. Moreover, we show that CD36, a multifunctional fatty acid transporter, connects the metabolic state of fibroblasts with their capacity for ECM regulation, as internalization and degradation of collagen-1 is abrogated in fibroblasts lacking CD36. Finally, restoring FAO and upregulating CD36 reduces ECM accumulation in murine skin fibrosis. These findings indicate that metabolic perturbation of ECM homeostasis may have broad implications for therapies aimed at ECM regulation, such as fibrosis, regenerative medicine, and ageing.
    DOI:  https://doi.org/10.1038/s42255-018-0008-5
  27. Autophagy. 2020 Jul 20.
    CALCOCO1 is a soluble reticulophagy receptor.
    Thaddaeus Mutugi Nthiga, Birendra Kumar Shrestha, Trond Lamark, Terje Johansen.
      The endoplasmic reticulum (ER) is the largest membrane-bound organelle in eukaryotic cells and plays critical roles in diverse processes in metabolism, signaling and intracellular organization. In response to stress stimuli such as nutrient deprivation, accumulation of misfolded proteins or exposure to chemicals, the ER increases in size through upregulated synthesis of its components to counteract the stress. To restore physiological size, the excess ER components are continuously dismantled and degraded by reticulophagy, a form of autophagy that targets, via adaptor molecules called reticulophagy receptors, specific ER portions to the lysosome for degradation. Previous studies have identified several ER resident proteins as reticulophagy receptors. In a recent study, we identified CALCOCO1 as a soluble reticulophagy receptor for the degradation of tubular ER in response to proteotoxic and starvation-induced stress. On the ER membrane, CALCOCO1 interacts with VAPA and VAPB via a FFAT-like motif and recruits autophagy machinery by binding directly to Atg8-family proteins via LIR and UDS interacting region (UIR) motifs acting co-dependently. Depletion of CALCOCO1 in cultured cells led to an impaired ER degradation during stress.
    Keywords:  Autophagy receptor; CALCOCO1; ER-phagy; FFAT motif; VAPA
    DOI:  https://doi.org/10.1080/15548627.2020.1797289
  28. Cancer Cell. 2020 Jul 07. pii: S1535-6108(20)30310-X. [Epub ahead of print]
    Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma.
    Lindsay M LaFave, Vinay K Kartha, Sai Ma, Kevin Meli, Isabella Del Priore, Caleb Lareau, Santiago Naranjo, Peter M K Westcott, Fabiana M Duarte, Venkat Sankar, Zachary Chiang, Alison Brack, Travis Law, Haley Hauck, Annalisa Okimoto, Aviv Regev, Jason D Buenrostro, Tyler Jacks.
      Regulatory networks that maintain functional, differentiated cell states are often dysregulated in tumor development. Here, we use single-cell epigenomics to profile chromatin state transitions in a mouse model of lung adenocarcinoma (LUAD). We identify an epigenomic continuum representing loss of cellular identity and progression toward a metastatic state. We define co-accessible regulatory programs and infer key activating and repressive chromatin regulators of these cell states. Among these co-accessibility programs, we identify a pre-metastatic transition, characterized by activation of RUNX transcription factors, which mediates extracellular matrix remodeling to promote metastasis and is predictive of survival across human LUAD patients. Together, these results demonstrate the power of single-cell epigenomics to identify regulatory programs to uncover mechanisms and key biomarkers of tumor progression.
    Keywords:  cancer; epigenomics; epithelial-to-mesenchymal transition; metastasis; non-small cell lung cancer; single cell
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.006
  29. Nat Metab. 2020 Jul;2(7): 566-571
    Lactate: the ugly duckling of energy metabolism.
    Joshua D Rabinowitz, Sven Enerbäck.
      Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism.
    DOI:  https://doi.org/10.1038/s42255-020-0243-4
  30. Elife. 2020 Jul 21. pii: e54066. [Epub ahead of print]9
    Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation.
    Ashna Alladin, Lucas Chaible, Lucia Garcia Del Valle, Reither Sabine, Monika Loeschinger, Malte Wachsmuth, Jean-Karim Hériché, Christian Tischer, Martin Jechlinger.
      Cancer clone evolution takes place within tissue ecosystem habitats. But, how exactly tumors arise from a few malignant cells within an intact epithelium is a central, yet unanswered question. This is mainly due to the inaccessibility of this process to longitudinal imaging together with a lack of systems that model the progression of a fraction of transformed cells within a tissue. Here, we developed a new methodology based on primary mouse mammary epithelial acini, where oncogenes can be switched on in single cells within an otherwise normal epithelial cell layer. We combine this stochastic breast tumor induction model with inverted light-sheet imaging to study single-cell behavior for up to four days and analyze cell fates utilizing a newly developed image-data analysis workflow. The power of this integrated approach is illustrated by us finding that small local clusters of transformed cells form tumors while isolated transformed cells do not.
    Keywords:  cancer biology; cell biology; interaction requirements for tumor initiation; light sheet imaging technology; mouse; organoid technology of primary mammary epithelium; scalable big image data analysis pipeline; tractable tumor induction system
    DOI:  https://doi.org/10.7554/eLife.54066
  31. Nat Metab. 2020 Jun;2(6): 499-513
    Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.
    Michael Aregger, Keith A Lawson, Maximillian Billmann, Michael Costanzo, Amy H Y Tong, Katherine Chan, Mahfuzur Rahman, Kevin R Brown, Catherine Ross, Matej Usaj, Lucy Nedyalkova, Olga Sizova, Andrea Habsid, Judy Pawling, Zhen-Yuan Lin, Hala Abdouni, Cassandra J Wong, Alexander Weiss, Patricia Mero, James W Dennis, Anne-Claude Gingras, Chad L Myers, Brenda J Andrews, Charles Boone, Jason Moffat.
      The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases, including cancer. Because cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to the loss of de novo fatty acid biosynthesis. Here, we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in fatty acid synthase (FASN), whose product catalyses the formation of long-chain fatty acids. FASN-mutant cells show a strong dependence on lipid uptake that is reflected in negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient in other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2 and ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene C12orf49 (which we call LUR1) in regulation of exogenous lipid uptake through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.
    DOI:  https://doi.org/10.1038/s42255-020-0211-z
  32. Science. 2020 Jul 24. 369(6502): 403-413
    The activities of drug inactive ingredients on biological targets.
    Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread, Barun Bhhatarai, Guiqing Liang, Hong Jin, S Nassir Ghaemi, Samuel Slocum, Katalin V Lukacs, John J Irwin, Ellen L Berg, Kathleen M Giacomini, Bryan L Roth, Brian K Shoichet, Laszlo Urban.
      Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.
    DOI:  https://doi.org/10.1126/science.aaz9906
  33. Science. 2020 Jul 24. 369(6502): 378
    Beth Cindy Levine (1960-2020).
    Herbert W Virgin, Ana Maria Cuervo, Ramnik J Xavier.
      
    DOI:  https://doi.org/10.1126/science.abd6216
  34. J Clin Oncol. 2020 Jul 24. JCO2000590
    Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma.
    Eric Van Cutsem, Margaret A Tempero, Darren Sigal, Do-Youn Oh, Nicola Fazio, Teresa Macarulla, Erika Hitre, Pascal Hammel, Andrew E Hendifar, Susan E Bates, Chung-Pin Li, Sunil R Hingorani, Christelle de la Fouchardiere, Anup Kasi, Volker Heinemann, Anthony Maraveyas, Nathan Bahary, Laura Layos, Vaibhav Sahai, Lei Zheng, Jill Lacy, Joon Oh Park, Fabienne Portales, Paul Oberstein, Wilson Wu, Dimitrios Chondros, Andrea J Bullock, .
      PURPOSE: To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA).PATIENTS AND METHODS: HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1.
    RESULTS: At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%).
    CONCLUSION: The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.
    DOI:  https://doi.org/10.1200/JCO.20.00590
  35. Nat Metab. 2020 May;2(5): 432-446
    Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.
    Accalia Fu, Juan Carlos Alvarez-Perez, Daina Avizonis, Tatsuya Kin, Scott B Ficarro, Dong Wook Choi, Esra Karakose, Mehmet G Badur, Lindsay Evans, Carolina Rosselot, Gaelle Bridon, Gregory H Bird, Hyuk-Soo Seo, Sirano Dhe-Paganon, Jurre J Kamphorst, Andrew F Stewart, A M James Shapiro, Jarrod A Marto, Loren D Walensky, Russell G Jones, Adolfo Garcia-Ocana, Nika N Danial.
      Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC-urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism.
    DOI:  https://doi.org/10.1038/s42255-020-0199-4
  36. CA Cancer J Clin. 2020 Jul 19.
    Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma.
    Aaron J Grossberg, Linda C Chu, Christopher R Deig, Eliot K Fishman, William L Hwang, Anirban Maitra, Daniel L Marks, Arnav Mehta, Nima Nabavizadeh, Diane M Simeone, Colin D Weekes, Charles R Thomas.
      Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.
    Keywords:  cachexia; epidemiology; health outcomes; pancreatic neoplasms; screening and early detection
    DOI:  https://doi.org/10.3322/caac.21626
  37. Nat Commun. 2020 Jul 20. 11(1): 3651
    H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients.
    Kolja Schleich, Julia Kase, Jan R Dörr, Saskia Trescher, Animesh Bhattacharya, Yong Yu, Elizabeth M Wailes, Dorothy N Y Fan, Philipp Lohneis, Maja Milanovic, Andrea Lau, Dido Lenze, Michael Hummel, Bjoern Chapuy, Ulf Leser, Maurice Reimann, Soyoung Lee, Clemens A Schmitt.
      Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles - such as cellular senescence - remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas - with and without defined genetic lesions - recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.
    DOI:  https://doi.org/10.1038/s41467-020-17467-z
  38. Nat Metab. 2020 Jan;2(1): 50-61
    Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue.
    Emily L Goldberg, Irina Shchukina, Jennifer L Asher, Sviatoslav Sidorov, Maxim N Artyomov, Vishwa Deep Dixit.
      Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid-driven fuel use to reduced adipose tissue inflammation.
    DOI:  https://doi.org/10.1038/s42255-019-0160-6
  39. Nat Metab. 2019 Oct;1(10): 947-957
    Control strategies in systemic metabolism.
    Jessica Ye, Ruslan Medzhitov.
      Metabolic control systems coordinate myriad processes across the cellular, tissue and organismal levels to optimize the allocation of limited supplies across multiple, often competing, metabolic demands. As such, the regulation of metabolism can be analysed from the perspective of the economic theory of supply and demand. Here, we discuss how such analyses can provide new insights into the logic of metabolic control. In particular, we suggest that, in addition to being subject to well-appreciated homeostatic control, metabolism is subject to supply-driven and demand-driven controls, each operated by a dedicated set of signals throughout various physiological states, including inflammation. Furthermore, we argue that systemic homeostasis is a derived feature that evolved from the control systems that monitor metabolic supply and demand.
    DOI:  https://doi.org/10.1038/s42255-019-0118-8
  40. Nat Metab. 2020 Mar;2(3): 278-289
    Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism.
    Gurpreet S Baht, Akshay Bareja, David E Lee, Rajesh R Rao, Rong Huang, Janet L Huebner, David B Bartlett, Corey R Hart, Jason R Gibson, Ian R Lanza, Virginia B Kraus, Simon G Gregory, Bruce M Spiegelman, James P White.
      The immune system plays a multifunctional role throughout the regenerative process, regulating both pro-/anti-inflammatory phases and progenitor cell function. In the present study, we identify the myokine/cytokine Meteorin-like (Metrnl) as a critical regulator of muscle regeneration. Mice genetically lacking Metrnl have impaired muscle regeneration associated with a reduction in immune cell infiltration and an inability to transition towards an anti-inflammatory phenotype. Isochronic parabiosis, joining wild-type and whole-body Metrnl knock-out (KO) mice, returns Metrnl expression in the injured muscle and improves muscle repair, providing supportive evidence for Metrnl secretion from infiltrating immune cells. Macrophage-specific Metrnl KO mice are also deficient in muscle repair. During muscle regeneration, Metrnl works, in part, through Stat3 activation in macrophages, resulting in differentiation to an anti-inflammatory phenotype. With regard to myogenesis, Metrnl induces macrophage-dependent insulin-like growth factor 1 production, which has a direct effect on primary muscle satellite cell proliferation. Perturbations in this pathway inhibit efficacy of Metrnl in the regenerative process. Together, these studies identify Metrnl as an important regulator of muscle regeneration and a potential therapeutic target to enhance tissue repair.
    DOI:  https://doi.org/10.1038/s42255-020-0184-y
  41. Nat Metab. 2020 Apr;2(4): 318-334
    NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.
    Douglas B Fox, Nina Marie G Garcia, Brock J McKinney, Ryan Lupo, Laura C Noteware, Rachel Newcomb, Juan Liu, Jason W Locasale, Matthew D Hirschey, James V Alvarez.
      The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.
    Keywords:  Breast cancer recurrence; Her2; NRF2; ROS; Residual disease; Tumor metabolism
    DOI:  https://doi.org/10.1038/s42255-020-0191-z
  42. Elife. 2020 Jul 21. pii: e55963. [Epub ahead of print]9
    Molecular determinants of large cargo transport into the nucleus.
    Giulia Paci, Tiantian Zheng, Joana Caria, Anton Zilman, Edward A Lemke.
      Nucleocytoplasmic transport is tightly regulated by the nuclear pore complex (NPC). Among the thousands of molecules that cross the NPC, even very large (>15 nm) cargoes such as pathogens, mRNAs and pre-ribosomes can pass the NPC intact. For these cargoes, there is little quantitative understanding of the requirements for their nuclear import, especially the role of multivalent binding to transport receptors via nuclear localisation sequences (NLSs) and the effect of size on import efficiency. Here, we assayed nuclear import kinetics of 30 large cargo models based on four capsid-like particles in the size range of 17-36 nm, with tuneable numbers of up to 240 NLSs. We show that the requirements for nuclear transport can be recapitulated by a simple two-parameter biophysical model that correlates the import flux with the energetics of large cargo transport through the NPC. Together, our results reveal key molecular determinants of large cargo import in cells.
    Keywords:  E. coli; NLS; capsid; cell biology; human; import kinetics; large cargo; molecular biophysics; nuclear transport; permeabilized cells; structural biology
    DOI:  https://doi.org/10.7554/eLife.55963
  43. Proc Natl Acad Sci U S A. 2020 Jul 23. pii: 202003236. [Epub ahead of print]
    Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1.
    Wesley Peng, Yvette C Wong, Dimitri Krainc.
      Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
    Keywords:  TRPML1; calcium; lysosomal storage disorder; mitochondria–lysosome contacts; interorganelle membrane contact sites
    DOI:  https://doi.org/10.1073/pnas.2003236117
  44. Nature. 2020 Jul 22.
    A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue.
    Putianqi Wang, Ken H Loh, Michelle Wu, Donald A Morgan, Marc Schneeberger, Xiaofei Yu, Jingyi Chi, Christin Kosse, Damian Kim, Kamal Rahmouni, Paul Cohen, Jeffrey Friedman.
      Mutations in the leptin gene (ob) result in a metabolic disorder that includes severe obesity1, and defects in thermogenesis2 and lipolysis3, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that ob/ob mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of ob/ob mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNFPVH). Deletion of BDNFPVH blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-020-2527-y
  45. Nat Metab. 2020 Jul;2(7): 620-634
    Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3.
    Shannon M Reilly, Chao-Wei Hung, Maryam Ahmadian, Peng Zhao, Omer Keinan, Andrew V Gomez, Julia H DeLuca, Benyamin Dadpey, Donald Lu, Jessica Zaid, BreAnne Poirier, Xiaoling Peng, Ruth T Yu, Michael Downes, Christopher Liddle, Ronald M Evans, Anne N Murphy, Alan R Saltiel.
      Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of β-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.
    DOI:  https://doi.org/10.1038/s42255-020-0217-6
  46. J Exp Med. 2020 Sep 07. pii: e20191206. [Epub ahead of print]217(9):
    Membrane budding is a major mechanism of in vivo platelet biogenesis.
    Kathryn S Potts, Alison Farley, Caleb A Dawson, Joel Rimes, Christine Biben, Carolyn de Graaf, Margaret A Potts, Olivia J Stonehouse, Amandine Carmagnac, Pradnya Gangatirkar, Emma C Josefsson, Casey Anttila, Daniela Amann-Zalcenstein, Shalin Naik, Warren S Alexander, Douglas J Hilton, Edwin D Hawkins, Samir Taoudi.
      How platelets are produced by megakaryocytes in vivo remains controversial despite more than a century of investigation. Megakaryocytes readily produce proplatelet structures in vitro; however, visualization of platelet release from proplatelets in vivo has remained elusive. We show that within the native prenatal and adult environments, the frequency and rate of proplatelet formation is incompatible with the physiological demands of platelet replacement. We resolve this inconsistency by performing in-depth analysis of plasma membrane budding, a cellular process that has previously been dismissed as a source of platelet production. Our studies demonstrate that membrane budding results in the sustained release of platelets directly into the peripheral circulation during both fetal and adult life without induction of cell death or proplatelet formation. In support of this model, we demonstrate that in mice deficient for NF-E2 (the thrombopoietic master regulator), the absence of membrane budding correlates with failure of in vivo platelet production. Accordingly, we propose that membrane budding, rather than proplatelet formation, supplies the majority of the platelet biomass.
    DOI:  https://doi.org/10.1084/jem.20191206
  47. Proc Natl Acad Sci U S A. 2020 Jul 21. pii: 202004408. [Epub ahead of print]
    Lipid sponge droplets as programmable synthetic organelles.
    Ahanjit Bhattacharya, Henrike Niederholtmeyer, Kira A Podolsky, Rupak Bhattacharya, Jing-Jin Song, Roberto J Brea, Chu-Hsien Tsai, Sunil K Sinha, Neal K Devaraj.
      Living cells segregate molecules and reactions in various subcellular compartments known as organelles. Spatial organization is likely essential for expanding the biochemical functions of synthetic reaction systems, including artificial cells. Many studies have attempted to mimic organelle functions using lamellar membrane-bound vesicles. However, vesicles typically suffer from highly limited transport across the membranes and an inability to mimic the dense membrane networks typically found in organelles such as the endoplasmic reticulum. Here, we describe programmable synthetic organelles based on highly stable nonlamellar sponge phase droplets that spontaneously assemble from a single-chain galactolipid and nonionic detergents. Due to their nanoporous structure, lipid sponge droplets readily exchange materials with the surrounding environment. In addition, the sponge phase contains a dense network of lipid bilayers and nanometric aqueous channels, which allows different classes of molecules to partition based on their size, polarity, and specific binding motifs. The sequestration of biologically relevant macromolecules can be programmed by the addition of suitably functionalized amphiphiles to the droplets. We demonstrate that droplets can harbor functional soluble and transmembrane proteins, allowing for the colocalization and concentration of enzymes and substrates to enhance reaction rates. Droplets protect bound proteins from proteases, and these interactions can be engineered to be reversible and optically controlled. Our results show that lipid sponge droplets permit the facile integration of membrane-rich environments and self-assembling spatial organization with biochemical reaction systems.
    Keywords:  artificial cell; lipids; membrane; organelle; sponge phase
    DOI:  https://doi.org/10.1073/pnas.2004408117
  48. Proc Natl Acad Sci U S A. 2020 Jul 21. pii: 202006177. [Epub ahead of print]
    Exoplanet secondary atmosphere loss and revival.
    Edwin S Kite, Megan N Barnett.
      The next step on the path toward another Earth is to find atmospheres similar to those of Earth and Venus-high-molecular-weight (secondary) atmospheres-on rocky exoplanets. Many rocky exoplanets are born with thick (>10 kbar) H2-dominated atmospheres but subsequently lose their H2; this process has no known Solar System analog. We study the consequences of early loss of a thick H2 atmosphere for subsequent occurrence of a high-molecular-weight atmosphere using a simple model of atmosphere evolution (including atmosphere loss to space, magma ocean crystallization, and volcanic outgassing). We also calculate atmosphere survival for rocky worlds that start with no H2 Our results imply that most rocky exoplanets orbiting closer to their star than the habitable zone that were formed with thick H2-dominated atmospheres lack high-molecular-weight atmospheres today. During early magma ocean crystallization, high-molecular-weight species usually do not form long-lived high-molecular-weight atmospheres; instead, they are lost to space alongside H2 This early volatile depletion also makes it more difficult for later volcanic outgassing to revive the atmosphere. However, atmospheres should persist on worlds that start with abundant volatiles (for example, water worlds). Our results imply that in order to find high-molecular-weight atmospheres on warm exoplanets orbiting M-stars, we should target worlds that formed H2-poor, that have anomalously large radii, or that orbit less active stars.
    Keywords:  atmospheric evolution; exoplanets; planetary science
    DOI:  https://doi.org/10.1073/pnas.2006177117
  49. Nat Rev Nephrol. 2020 Jul 23.
    Autophagy in kidney homeostasis and disease.
    Chengyuan Tang, Man J Livingston, Zhiwen Liu, Zheng Dong.
      Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux - mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.
    DOI:  https://doi.org/10.1038/s41581-020-0309-2
  50. Autophagy. 2020 Jul 20.
    Ramping up the autophagy-lysosome system to cope with osmotic stress.
    Tania López-Hernández, Tanja Maritzen, Volker Haucke.
      Osmotic stress is a critical challenge for mammalian cells as loss of water triggered by a hyperosmotic environment promotes harmful protein aggregation and impairs cell survival. How the degradative capacity of cells, in particular the macroautophagy/autophagy-lysosome system, is adapted to meet the proteolytic demands induced by osmotic challenge remains poorly understood. We have identified a hitherto unknown pathway that is activated by hyperosmotic stress and serves to link alterations in cellular ion homeostasis to the induction of autophagy and lysosomal gene expression and, thereby, to lysosome biogenesis.
    Keywords:  CLEAR network; TFEB; endocytosis; ion honeostasis; lysosome; macroautophagy; osmotic stress; proteostasis
    DOI:  https://doi.org/10.1080/15548627.2020.1798065
  51. EMBO Mol Med. 2020 Jul 20. e11416
    Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.
    Luana Schito, Sergio Rey, Ping Xu, Shan Man, William Cruz-Muñoz, Robert S Kerbel.
      Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
    Keywords:  HIF-1; breast cancer; colon cancer; hypoxia; low-dose metronomic
    DOI:  https://doi.org/10.15252/emmm.201911416
  52. Nat Metab. 2020 Jan;2(1): 81-96
    Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine.
    Kenji Ohshima, Satoshi Nojima, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Yumiko Hori, Moyu Taniguchi, Yutaka Umakoshi, Daisuke Okuzaki, Naoki Wada, Jun-Ichiro Ikeda, Eiichiro Fukusaki, Eiichi Morii.
      Serine racemase (SRR) catalyses not only the racemization but also the dehydration of L-serine and D-serine, resulting in the formation of pyruvate and ammonia. Although SRR activity is important in the central nervous system, SRR has not been linked to cancer metabolism before. Here we show that SRR supports proliferation of colorectal-cancer cells. We find that SRR expression is upregulated in colorectal adenoma and adenocarcinoma lesions compared with non-neoplastic mucosa in human colorectal-cancer specimens. SRR-mediated dehydration of serine contributes to the pyruvate pool in colon-cancer cells, enhances proliferation, maintains mitochondrial mass and increases basal reactive oxygen species production, which has anti-apoptotic effects. Moreover, SRR promotes acetylation of histone H3 by maintaining intracellular acetyl-CoA levels. Inhibition of SRR suppresses growth of colorectal tumours in mice and augments the efficacy of 5-fluorouracil treatment. Our findings highlight a previously unknown mechanism through which a racemase supports cancer-cell growth and suggest that SRR might be a molecular target for colorectal-cancer therapy.
    DOI:  https://doi.org/10.1038/s42255-019-0156-2
  53. Nat Rev Endocrinol. 2020 Jul 20.
    Mechanism for the effects of FGF21.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-020-0396-y
  54. Nat Chem Biol. 2020 Jul 23.
    A stress-free stress response.
    Nadia Cummins, Rebecca C Taylor.
      
    DOI:  https://doi.org/10.1038/s41589-020-0616-8
  55. Nat Metab. 2019 Jul;1(7): 666-675
    Role and therapeutic potential of dietary ketone bodies in lymph vessel growth.
    Melissa García-Caballero, Annalisa Zecchin, Joris Souffreau, Anh-Co Khanh Truong, Laure-Anne Teuwen, Wesley Vermaelen, Rosa Martín-Pérez, Pauline de Zeeuw, Ann Bouché, Stefan Vinckier, Ivo Cornelissen, Guy Eelen, Bart Ghesquière, Massimiliano Mazzone, Mieke Dewerchin, Peter Carmeliet.
      Lymphatic vessels (LVs), lined by lymphatic endothelial cells (LECs), are indispensable for life1. However, the role of metabolism in LECs has been incompletely elucidated. In the present study, it is reported that LEC-specific loss of OXCT1, a key enzyme of ketone body oxidation2, reduces LEC proliferation, migration and vessel sprouting in vitro and impairs lymphangiogenesis in development and disease in Prox1ΔOXCT1 mice. Mechanistically, OXCT1 silencing lowers acetyl-CoA levels, tricarboxylic acid cycle metabolite pools, and nucleotide precursor and deoxynucleotide triphosphate levels required for LEC proliferation. Ketone body supplementation to LECs induces the opposite effects. Notably, elevation of lymph ketone body levels by a high-fat, low-carbohydrate ketogenic diet or by administration of the ketone body β-hydroxybutyrate increases lymphangiogenesis after corneal injury and myocardial infarction. Intriguingly, in a mouse model of microsurgical ablation of LVs in the tail, which repeats features of acquired lymphoedema in humans, the ketogenic diet improves LV function and growth, reduces infiltration of anti-lymphangiogenic immune cells and decreases oedema, suggesting a novel dietary therapeutic opportunity.
    DOI:  https://doi.org/10.1038/s42255-019-0087-y
  56. Cancer Res. 2020 Jul 21. pii: canres.0754.2020. [Epub ahead of print]
    Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma.
    Yi Xiao, Rosanna Clima, Jonas Busch, Anja Rabien, Ergin Kilic, Sonia L Villegas, Bernd Timmermann, Marcella Attimonelli, Klaus Jung, David Meierhofer.
      Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO) are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in RO but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multi-omic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in RO. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and RO and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0754
  57. Nat Metab. 2020 Mar 30.
    Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function.
    James Frampton, Kevin G Murphy, Gary Frost, Edward S Chambers.
      A key metabolic activity of the gut microbiota is the fermentation of non-digestible carbohydrate, which generates short-chain fatty acids (SCFAs) as the principal end products. SCFAs are absorbed from the gut lumen and modulate host metabolic responses at different organ sites. Evidence suggests that these organ sites include skeletal muscle, the largest organ in humans, which plays a pivotal role in whole-body energy metabolism. In this Review, we evaluate the evidence indicating that SCFAs mediate metabolic cross-talk between the gut microbiota and skeletal muscle. We discuss the effects of three primary SCFAs (acetate, propionate and butyrate) on lipid, carbohydrate and protein metabolism in skeletal muscle, and we consider the potential mechanisms involved. Furthermore, we highlight the emerging roles of these gut-derived metabolites in skeletal muscle function and exercise capacity, present limitations in current knowledge and provide suggestions for future work.
    DOI:  https://doi.org/10.1038/s42255-020-0188-7
  58. J Clin Invest. 2020 Jul 21. pii: 133935. [Epub ahead of print]
    BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.
    Valerie A C M Koeken, L Charlotte J de Bree, Vera P Mourits, Simone Jcfm Moorlag, Jona Walk, Branko Cirovic, Rob Jw Arts, Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Leo Ab Joosten, Christine Stabell Benn, Reinout van Crevel, Mihai Netea.
      BACKGROUND: Induction of innate immune memory, also termed trained immunity, by the anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known: while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODS: We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis and Staphylococcus aureus induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.
    RESULTS: While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in three smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.
    CONCLUSION: The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.
    FUNDING: This study was funded by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant (TRAIN-OLD nr. 833247).
    Keywords:  Cytokines; Immunology; Innate immunity; Monocytes; Vaccines
    DOI:  https://doi.org/10.1172/JCI133935
  59. Nat Protoc. 2020 Jul 20.
    Organotypic culture assays for murine and human primary and metastatic-site tumors.
    Veena Padmanaban, Eloise M Grasset, Neil M Neumann, Andrew K Fraser, Elodie Henriet, William Matsui, Phuoc T Tran, Kevin J Cheung, Dan Georgess, Andrew J Ewald.
      Cancer invasion and metastasis are challenging to study in vivo since they occur deep inside the body over extended time periods. Organotypic 3D culture of fresh tumor tissue enables convenient real-time imaging, genetic and microenvironmental manipulation and molecular analysis. Here, we provide detailed protocols to isolate and culture heterogenous organoids from murine and human primary and metastatic site tumors. The time required to isolate organoids can vary based on the tissue and organ type but typically takes <7 h. We describe a suite of assays that model specific aspects of metastasis, including proliferation, survival, invasion, dissemination and colony formation. We also specify comprehensive protocols for downstream applications of organotypic cultures that will allow users to (i) test the role of specific genes in regulating various cellular processes, (ii) distinguish the contributions of several microenvironmental factors and (iii) test the effects of novel therapeutics.
    DOI:  https://doi.org/10.1038/s41596-020-0335-3
  60. Nat Metab. 2019 Aug;1(8): 830-843
    Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.
    Jasper M A de Jong, Wenfei Sun, Nuno D Pires, Andrea Frontini, Miroslav Balaz, Naja Z Jespersen, Amir Feizi, Katarina Petrovic, Alexander W Fischer, Muhammad Hamza Bokhari, Tarja Niemi, Pirjo Nuutila, Saverio Cinti, Søren Nielsen, Camilla Scheele, Kirsi Virtanen, Barbara Cannon, Jan Nedergaard, Christian Wolfrum, Natasa Petrovic.
      Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
    DOI:  https://doi.org/10.1038/s42255-019-0101-4
  61. Nat Metab. 2019 Dec;1(12): 1202-1208
    Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss.
    Emily A Day, Rebecca J Ford, Brennan K Smith, Pedrum Mohammadi-Shemirani, Marisa R Morrow, Robert M Gutgesell, Rachel Lu, Amogelang R Raphenya, Mostafa Kabiri, Andrew G McArthur, Natalia McInnes, Sibylle Hess, Guillaume Paré, Hertzel C Gerstein, Gregory R Steinberg.
      Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.
    DOI:  https://doi.org/10.1038/s42255-019-0146-4
  62. Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30544-X. [Epub ahead of print]54(2): 156-170
    Metabolites Regulate Cell Signaling and Growth via Covalent Modification of Proteins.
    Gianluca Figlia, Philipp Willnow, Aurelio A Teleman.
      Metabolites affect cell growth in two different ways. First, they serve as building blocks for biomass accumulation. Second, metabolites regulate the activity of growth-relevant signaling pathways. They do so in part by covalently attaching to proteins, thereby generating post-translational modifications (PTMs) that affect protein function, the focus of this Perspective. Recent advances in mass spectrometry have revealed a wide variety of such metabolites, including lipids, amino acids, Coenzyme-A, acetate, malonate, and lactate to name a few. An active area of research is to understand which modifications affect protein function and how they do so. In many cases, the cellular levels of these metabolites affect the stoichiometry of the corresponding PTMs, providing a direct link between cell metabolism and the control of cell signaling, transcription, and cell growth.
    Keywords:  O-GlcNAc; YAP; acetylation; autophagy; crotonylation; glutathionylation; hippo; mTORC1; malonylation; methylation; palmitoylation
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.036
  63. Nat Metab. 2020 Jul;2(7): 603-611
    Selenium detoxification is required for cancer-cell survival.
    Anne E Carlisle, Namgyu Lee, Asia N Matthew-Onabanjo, Meghan E Spears, Sung Jin Park, Daniel Youkana, Mihir B Doshi, Austin Peppers, Rui Li, Alexander B Joseph, Miles Smith, Karl Simin, Lihua Julie Zhu, Paul L Greer, Leslie M Shaw, Dohoon Kim.
      The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such as glutathione peroxidases and thioredoxin reductases1,2. Here, we show that selenophosphate synthetase 2 (SEPHS2), an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal, cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. Accordingly, we find that SEPHS2 protein levels are elevated in samples from people with breast cancer, and that loss of SEPHS2 impairs growth of orthotopic mammary-tumour xenografts in mice. Collectively, our results identify a vulnerability of cancer cells and define the role of selenium metabolism in cancer.
    DOI:  https://doi.org/10.1038/s42255-020-0224-7
  64. Cell Discov. 2020 ;6 48
    Defining relative mutational difficulty to understand cancer formation.
    Lin Shan, Jiao Yu, Zhengjin He, Shishuang Chen, Mingxian Liu, Hongyu Ding, Liang Xu, Jie Zhao, Ailing Yang, Hai Jiang.
      Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here, we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN, and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such a parameter, we can bring new angles to understanding cancer formation.
    Keywords:  Cancer genetics; Cancer prevention
    DOI:  https://doi.org/10.1038/s41421-020-0177-8
  65. Cell Res. 2020 Jul 24.
    Metabolic signaling in T cells.
    Justin A Shyer, Richard A Flavell, Will Bailis.
      The maintenance of organismal homeostasis requires partitioning and transport of biochemical molecules between organ systems, their composite cells, and subcellular organelles. Although transcriptional programming undeniably defines the functional state of cells and tissues, underlying biochemical networks are intricately intertwined with transcriptional, translational, and post-translational regulation. Studies of the metabolic regulation of immunity have elegantly illustrated this phenomenon. The cells of the immune system interface with a diverse set of environmental conditions. Circulating immune cells perfuse peripheral organs in the blood and lymph, patrolling for pathogen invasion. Resident immune cells remain in tissues and play more newly appreciated roles in tissue homeostasis and immunity. Each of these cell populations interacts with unique and dynamic tissue environments, which vary greatly in biochemical composition. Furthermore, the effector response of immune cells to a diverse set of activating cues requires unique cellular adaptations to supply the requisite biochemical landscape. In this review, we examine the role of spatial partitioning of metabolic processes in immune function. We focus on studies of lymphocyte metabolism, with reference to the greater immunometabolism literature when appropriate to illustrate this concept.
    DOI:  https://doi.org/10.1038/s41422-020-0379-5
  66. Cell Rep. 2020 Jul 21. pii: S2211-1247(20)30918-9. [Epub ahead of print]32(3): 107937
    Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine.
    Lotte Bruens, Saskia Inge Johanna Ellenbroek, Saskia Jacoba Elisabeth Suijkerbuijk, Maria Azkanaz, Alexander James Hale, Pim Toonen, Dustin James Flanagan, Owen James Sansom, Hugo Johannes Snippert, Jacco van Rheenen.
      Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.
    Keywords:  Lgr5; calorie restriction; competition; diet; intestine; mutation retention; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2020.107937
  67. Nat Metab. 2019 Dec;1(12): 1177-1188
    Inter-organ cross-talk in metabolic syndrome.
    Christina Priest, Peter Tontonoz.
      Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome.
    DOI:  https://doi.org/10.1038/s42255-019-0145-5
  68. Nat Metab. 2019 Feb;1(2): 261-275
    ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis.
    Yusuke Endo, Atsushi Onodera, Kazushige Obata-Ninomiya, Ryo Koyama-Nasu, Hikari K Asou, Toshihiro Ito, Takeshi Yamamoto, Toshio Kanno, Takahiro Nakajima, Kenji Ishiwata, Hirotaka Kanuka, Damon J Tumes, Toshinori Nakayama.
      Immunological memory is central to adaptive immunity and protection from disease. Changing metabolic demands as antigen-specific T cells transition from effector to memory cells have been well documented, but the cell-specific pathways and molecules that govern this transition are poorly defined. Here we show that genetic deletion of ACC1, a rate-limiting enzyme in fatty acid biosynthesis, enhances the formation of CD4+ T memory cells. ACC1-deficient effector helper T (Th) cells have similar metabolic signatures to wild-type memory Th cells, and expression of the gene encoding ACC1, Acaca, was inversely correlated with a memory gene signature in individual cells. Inhibition of ACC1 function enhances memory T cell formation during parasite infection in mice. Using single-cell analyses we identify a memory precursor-enriched population (CCR7hiCD137lo) present during early differentiation of effector CD4+ T cells. Our data indicate that fatty acid metabolism directs cell fate determination during the generation of memory CD4+ T cells.
    DOI:  https://doi.org/10.1038/s42255-018-0025-4
  69. Proc Natl Acad Sci U S A. 2020 Jul 20. pii: 202010103. [Epub ahead of print]
    Phosphoprotein-based biomarkers as predictors for cancer therapy.
    Angela M Carter, Chunfeng Tan, Karine Pozo, Rahul Telange, Roberto Molinaro, Ailan Guo, Enrica De Rosa, Jonathan O Martinez, Shanrong Zhang, Nilesh Kumar, Masaya Takahashi, Thorsten Wiederhold, Hans K Ghayee, Sarah C Oltmann, Karel Pacak, Eugene A Woltering, Kimmo J Hatanpaa, Fiemu E Nwariaku, Elizabeth G Grubbs, Anthony J Gill, Bruce Robinson, Frank Gillardon, Sushanth Reddy, Renata Jaskula-Sztul, James A Mobley, M Shahid Mukhtar, Ennio Tasciotti, Herbert Chen, James A Bibb.
      Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
    Keywords:  cyclin-dependent kinase 5; neuroendocrine tumors; predictive biomarkers
    DOI:  https://doi.org/10.1073/pnas.2010103117
  70. Cancer Metab. 2020 ;8 17
    Treatment of ErbB2 breast cancer by mitochondrial targeting.
    Sophia Eldad, Rachel Hertz, Gilad Vainer, Ann Saada, Jacob Bar-Tana.
      Background: ErbB2 breast cancer still remains an unmet need due to primary and/or acquired resistance to current treatment strategies. MEDICA compounds consist of synthetic long-chain α,ω-dicarboxylic acids previously reported to suppress breast cancer in PyMT transgenic mice.Methods: MEDICA efficacy and mode of action in the ErbB2 context was studied in ErbB2 transgenic mice and human breast cancer cells.
    Results: MEDICA treatment is shown here to suppress ErbB2 breast tumors and lung metastasis in ErbB2/neu MMTV transgenic mice, to suppress ErbB2/neu xenografts in nod/scid mice, and to suppress survival of AU565 and BT474 human ErbB2 breast cancer cells. Suppression of ErbB2 breast tumors by MEDICA is due to lipid raft disruption with loss of ErbB family members, including EGFR, ErbB2, and ErbB3. In addition, MEDICA inhibits mTORC1 activity, independently of abrogating the ErbB receptors and their signaling cascades. The double hit of MEDICA in abrogating ErbB and mTORC1 is partly accounted for by targeting mitochondria complex I.
    Conclusions: Mitochondrial targeting by MEDICA suppresses ErbB2 breast tumors and metastasis due to lipid raft disruption and inhibition of mTORC1 activity. Inhibition of mTORC1 activity by MEDICA avoids the resistance acquired by canonical mTORC1 inhibitors like rapalogs or mTOR kinase inhibitors.
    Keywords:  Breast cancer; ErbB2; Lipid rafts; Mitochondria; mTORC1
    DOI:  https://doi.org/10.1186/s40170-020-00223-8
  71. Nat Metab. 2020 Jun;2(6): 476-477
    Metabolic terminology: what's in a name?
    Mary-Ellen Harper, Mary-Elizabeth Patti.
      
    DOI:  https://doi.org/10.1038/s42255-020-0216-7
  72. Sci Adv. 2020 Jun;6(25): eabb2210
    Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition.
    Anne Fassl, Christopher Brain, Monther Abu-Remaileh, Iga Stukan, Deborah Butter, Piotr Stepien, Avery S Feit, Johann Bergholz, Wojciech Michowski, Tobias Otto, Qing Sheng, Alice Loo, Walter Michael, Ralph Tiedt, Carmine DeAngelis, Rachel Schiff, Baishan Jiang, Bojana Jovanovic, Karolina Nowak, Maria Ericsson, Michael Cameron, Nathanael Gray, Deborah Dillon, Jean J Zhao, David M Sabatini, Rinath Jeselsohn, Myles Brown, Kornelia Polyak, Piotr Sicinski.
      Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.
    DOI:  https://doi.org/10.1126/sciadv.abb2210
  73. Gastroenterology. 2020 Jul 15. pii: S0016-5085(20)34929-5. [Epub ahead of print]
    The Influence of Gut and Tumor Microbiome on Pancreatic Cancer Outcomes.
    Natalia Khalaf, Hashem El-Serag, Fasiha Kanwal, Johanna Chan.
      Pancreatic cancer is a highly fatal malignancy with overall 5-year survival of under 10%, within the context of increasing incidence rates worldwide (Clin Gastroenterol Hepatol 2020 Mar 5. pii: S1542-3565(20)30276-7 [Epub ahead of print]). Even among the minority of patients who are diagnosed with early stage disease and undergo resection, most survive less than 5 years (short-term survivors (STS), however a unique subset of patients survive >5 years post-surgery coined long-term survivors (LTS) (Clin Cancer Res 2015;21:1944-1950). Recent human and mice studies suggests that the gut microbiome may play a role in pancreatic cancer initiation and progression through immune system modulation (Cancer Discov 2018;8:403-416, Gastroenterology 2018;155:33-37). Intramural bacteria can also be detected within pancreatic tumor tissue and predict sensitivity to systemic cancer therapy (Science 2017;357:1156-1160). Riquelme et al. addressed this topic in work conducted at the University of Texas MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH) to study the association between tumor microbiome and survival using the pancreatic tumor microbiome of LTS vs. STS (Cell 2019;178:795-806).
    DOI:  https://doi.org/10.1053/j.gastro.2020.07.008
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