bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–06–04
48 papers selected by
Christian Frezza, Universität zu Köln
  1. Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
  2. Metabolism in the tumour cell and beyond.
  3. Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hurthle cell carcinoma of the thyroid.
  4. ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.
  5. Nutrient sensors and their crosstalk.
  6. Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.
  7. Nutritional control of developmental processes.
  8. Traject3d for studying 3D cellular heterogeneity.
  9. Liver and muscle circadian clocks cooperate to support glucose tolerance in mice.
  10. Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma.
  11. FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer.
  12. A critical appraisal of the relative contribution of tissue architecture, genetics, epigenetics and cell metabolism to carcinogenesis.
  13. A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.
  14. Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
  15. Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
  16. Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis.
  17. Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
  18. Spatial Analysis of Nucleotide Metabolism: From CRISPR Knockout Cancer Cells to MALDI Imaging of Tumors.
  19. Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.
  20. Real-Time Monitoring of Hydrogen Peroxide Levels in Yeast and Mammalian Cells.
  21. Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.
  22. The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming.
  23. Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver.
  24. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation.
  25. Ovol1/2 loss-induced epidermal defects elicit skin immune activation and alter global metabolism.
  26. Quantification and Tracing of Stable Isotope into Cysteine and Glutathione.
  27. The CD73 immune checkpoint promotes tumor cell metabolic fitness.
  28. Emerging field: O-GlcNAcylation in ferroptosis.
  29. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
  30. Circadian Regulation of Metabolism - Commitment to Health and Diseases.
  31. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.
  32. 13C Isotope Labeling and Mass Spectrometric Isotope Enrichment Analysis in Acute Brain Slices.
  33. An unexpected pathway to polyamines in pancreatic cancer.
  34. Cytochrome c oxidase biogenesis - from translation to early assembly of the core subunit COX1.
  35. Reversing pathological cell states: the road less travelled can extend the therapeutic horizon.
  36. Lipid droplets are a metabolic vulnerability in melanoma.
  37. Reporting on FH-deficient renal cell carcinoma using circulating succinylated metabolites.
  38. MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.
  39. Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α.
  40. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
  41. Deterministic evolution and stringent selection during preneoplasia.
  42. A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition.
  43. A metabolomic signature of decelerated physiological aging in human plasma.
  44. Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis.
  45. M1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development.
  46. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
  47. Is metabolism the magic bullet for targeted cancer therapy?
  48. MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer.
  1. Elife. 2023 May 31. pii: e81289. [Epub ahead of print]12
    Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
    Juan J Apiz Saab, Lindsey N Dzierozynski, Patrick B Jonker, Roya AminiTabrizi, Hardik Shah, Rosa Elena Menjivar, Andrew J Scott, Zeribe C Nwosu, Zhou Zhu, Riona N Chen, Moses Oh, Colin Sheehan, Daniel R Wahl, Marina Pasca di Magliano, Costas A Lyssiotis, Kay F Macleod, Christopher R Weber, Alexander Muir.
      Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (M. R. Sullivan, Danai, et al., 2019). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.81289
  2. Mol Oncol. 2023 May 27.
    Metabolism in the tumour cell and beyond.
    Arkaitz Carracedo.
      The process of cellular transformation encompasses the acquisition of key and distinctive features, commonly known as hallmarks of cancer. These hallmarks are supported by tumour-intrinsic molecular alterations as well as changes in the microenvironment. Cellular metabolism represents one of the most intimate connections between a cell and the environment. In turn, metabolic adaptation represents a research field of increasing interest in cancer biology. In this viewpoint, I will provide a panoramic perspective of the relevance and repercussions of metabolic alterations in tumours with non-exhaustive illustrative examples and speculate the prospects of cancer metabolism research.
    Keywords:  Cancer metabolism; anabolism; metabolic vulnerability; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13467
  3. Cancer Discov. 2023 Jun 01. pii: CD-22-0982. [Epub ahead of print]
    Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hurthle cell carcinoma of the thyroid.
    Anderson R Frank, Vicky Li, Spencer D Shelton, Jiwoong Kim, Gordon M Stott, Leonard M Neckers, Yang Xie, Noelle S Williams, Prashant Mishra, David G McFadden.
      A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hurthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a PDX model that small molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0982
  4. Cell Rep. 2023 May 26. pii: S2211-1247(23)00573-9. [Epub ahead of print]42(6): 112562
    ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.
    Marc Hennequart, Steven E Pilley, Christiaan F Labuschagne, Jack Coomes, Loic Mervant, Paul C Driscoll, Nathalie M Legrave, Younghwan Lee, Peter Kreuzaler, Benedict Macintyre, Yulia Panina, Julianna Blagih, David Stevenson, Douglas Strathdee, Deborah Schneider-Luftman, Eva Grönroos, Eric C Cheung, Mariia Yuneva, Charles Swanton, Karen H Vousden.
      Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes-aldehyde dehydrogenase 1 family member 2 (ALDH1L2)-produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling.
    Keywords:  ALDH1L2; CP: Cancer; CP: Metabolism; ROS; breast cancer; formate; formyl-methionine; metastasis; one-carbon metabolism; serine
    DOI:  https://doi.org/10.1016/j.celrep.2023.112562
  5. Exp Mol Med. 2023 Jun 01.
    Nutrient sensors and their crosstalk.
    Yulseung Sung, Ya Chun Yu, Jung Min Han.
      The macronutrients glucose, lipids, and amino acids are the major components that maintain life. The ability of cells to sense and respond to fluctuations in these nutrients is a crucial feature for survival. Nutrient-sensing pathways are thus developed to govern cellular energy and metabolic homeostasis and regulate diverse biological processes. Accordingly, perturbations in these sensing pathways are associated with a wide variety of pathologies, especially metabolic diseases. Molecular sensors are the core within these sensing pathways and have a certain degree of specificity and affinity to sense the intracellular fluctuation of each nutrient either by directly binding to that nutrient or indirectly binding to its surrogate molecules. Once the changes in nutrient levels are detected, sensors trigger signaling cascades to fine-tune cellular processes for energy and metabolic homeostasis, for example, by controlling uptake, de novo synthesis or catabolism of that nutrient. In this review, we summarize the major discoveries on nutrient-sensing pathways and explain how those sensors associated with each pathway respond to intracellular nutrient availability and how these mechanisms control metabolic processes. Later, we further discuss the crosstalk between these sensing pathways for each nutrient, which are intertwined to regulate overall intracellular nutrient/metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s12276-023-01006-z
  6. Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2217332120
    Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.
    Austin C Boese, JiHoon Kang, Jung Seok Hwang, Jaehyun Kim, Kiyoung Eun, Courteney M Malin, Kelly R Magliocca, Chaoyun Pan, Lingtao Jin, Sumin Kang.
      Although recent studies demonstrate active mitochondrial metabolism in cancers, the precise mechanisms through which mitochondrial factors contribute to cancer metastasis remain elusive. Through a customized mitochondrion RNAi screen, we identified succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) as a critical anoikis resistance and metastasis driver in human cancers. Mechanistically, SUCLA2, but not the alpha subunit of its enzyme complex, relocates from mitochondria to the cytosol upon cell detachment where SUCLA2 then binds to and promotes the formation of stress granules. SUCLA2-mediated stress granules facilitate the protein translation of antioxidant enzymes including catalase, which mitigates oxidative stress and renders cancer cells resistant to anoikis. We provide clinical evidence that SUCLA2 expression correlates with catalase levels as well as metastatic potential in lung and breast cancer patients. These findings not only implicate SUCLA2 as an anticancer target, but also provide insight into a unique, noncanonical function of SUCLA2 that cancer cells co-opt to metastasize.
    Keywords:  mitochondrial metabolism; redox homeostasis; stress granule; succinyl-CoA ligase; tumor metastasis
    DOI:  https://doi.org/10.1073/pnas.2217332120
  7. Development. 2023 Oct 15. pii: dev200623. [Epub ahead of print]150(20):
    Nutritional control of developmental processes.
    Jaroslav Ferenc, Aissam Ikmi.
      Nutritional and metabolic cues are integral to animal development. Organisms use them both as sustenance and environmental indicators, fueling, informing and influencing developmental decisions. Classical examples, such as the Warburg effect, clearly illustrate how genetic programs control metabolic changes. However, the way that nutrition and metabolism can also modulate or drive genetic programs to instruct developmental trajectories is much more elusive, owing to several difficulties including uncoupling permissive and instructive functions. Here, we discuss recent advancements in the field that highlight the developmental role of nutritional and metabolic cues across multiple levels of organismal complexity.
    Keywords:  Developmental plasticity; Developmental trajectories; Metabolic heterogeneity; Metabolic signaling; Nutrition; Nutritional control; Organ crosstalk; Resource allocation
    DOI:  https://doi.org/10.1242/dev.200623
  8. Nat Rev Cancer. 2023 Jun 02.
    Traject3d for studying 3D cellular heterogeneity.
    Eva C Freckmann.
      
    DOI:  https://doi.org/10.1038/s41568-023-00592-4
  9. Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00599-5. [Epub ahead of print]42(6): 112588
    Liver and muscle circadian clocks cooperate to support glucose tolerance in mice.
    Jacob G Smith, Kevin B Koronowski, Thomas Mortimer, Tomoki Sato, Carolina M Greco, Paul Petrus, Amandine Verlande, Siwei Chen, Muntaha Samad, Ekaterina Deyneka, Lavina Mathur, Ronnie Blazev, Jeffrey Molendijk, Arun Kumar, Oleg Deryagin, Mireia Vaca-Dempere, Valentina Sica, Peng Liu, Valerio Orlando, Benjamin L Parker, Pierre Baldi, Patrick-Simon Welz, Cholsoon Jang, Selma Masri, Salvador Aznar Benitah, Pura Muñoz-Cánoves, Paolo Sassone-Corsi.
      Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.
    Keywords:  Bmal1; CP: Metabolism; autonomy; circadian rhythms; endocrinology; glucose; inter-organ crosstalk; liver; metabolism; muscle; systems biology
    DOI:  https://doi.org/10.1016/j.celrep.2023.112588
  10. Cancer Discov. 2023 Jun 01. pii: CD-22-0976. [Epub ahead of print]
    Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma.
    Raj K Gopal, Venkata R Vantaku, Apekshya Panda, Bryn Reimer, Sneha Rath, Tsz-Leung To, Adam S Fisch, Murat Cetinbas, Maia Livneh, Michael J Calcaterra, Benjamin J Gigliotti, Kerry A Pierce, Clary B Clish, Dora Dias-Santagata, Peter M Sadow, Lori J Wirth, Gilbert H Daniels, Ruslan I Sadreyev, Sarah E Calvo, Sareh Parangi, Vamsi K Mootha.
      Oncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0976
  11. Cancer Discov. 2023 May 31. pii: CD-22-0874. [Epub ahead of print]
    FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer.
    Blake R Wilde, Nishma Chakraborty, Nedas Matulionis, Stephanie Hernandez, Daiki Ueno, Michayla E Gee, Edward D Esplin, Karen Ouyang, Keith Nykamp, Brian Shuch, Heather R Christofk.
      Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0874
  12. Prog Biophys Mol Biol. 2023 May 31. pii: S0079-6107(23)00056-1. [Epub ahead of print]
    A critical appraisal of the relative contribution of tissue architecture, genetics, epigenetics and cell metabolism to carcinogenesis.
    Thomas W Grunt, Gerwin Heller.
      Here we contrast several carcinogenesis models. The somatic-mutation-theory posits mutations as main causes of malignancy. However, inconsistencies led to alternative explanations. For example, the tissue-organization-field-theory considers disrupted tissue-architecture as main cause. Both models can be reconciled using systems-biology-approaches, according to which tumors hover in states of self-organized criticality between order and chaos, are emergent results of multiple deviations and are subject to general laws of nature: inevitable variation(mutation) explainable by increased entropy(second-law-of-thermodynamics) or indeterminate decoherence upon measurement of superposed quantum systems(quantum mechanics), followed by Darwinian-selection. Genomic expression is regulated by epigenetics. Both systems cooperate. So cancer is neither just a mutational nor an epigenetic problem. Rather, epigenetics links environmental cues to endogenous genetics engendering a regulatory machinery that encompasses specific cancer-metabolic-networks. Interestingly, mutations occur at all levels of this machinery (oncogenes/tumor-suppressors, epigenetic-modifiers, structure-genes, metabolic-genes). Therefore, in most cases, DNA mutations may be the initial and crucial cancer-promoting triggers.
    Keywords:  Cancer metabolism; Entropy; Epigenetics; Mutation; Quantum effects; Self-organized criticality; Somatic mutation theory; Tissue organization field theory
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2023.05.004
  13. Mol Syst Biol. 2023 Jun 01. e11267
    A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.
    Amandine Moretton, Savvas Kourtis, Antoni Gañez Zapater, Chiara Calabrò, Maria Lorena Espinar Calvo, Frédéric Fontaine, Evangelia Darai, Etna Abad Cortel, Samuel Block, Laura Pascual-Reguant, Natalia Pardo-Lorente, Ritobrata Ghose, Matthew G Vander Heiden, Ana Janic, André C Müller, Joanna I Loizou, Sara Sdelci.
      While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.
    Keywords:  DNA damage response; Peroxiredoxin 1; aspartate metabolism; electron transport chain; reactive oxygen species scavenging
    DOI:  https://doi.org/10.15252/msb.202211267
  14. Nat Cancer. 2023 May 29.
    Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
    Pravat Kumar Parida, Mauricio Marquez-Palencia, Suvranil Ghosh, Nitin Khandelwal, Kangsan Kim, Vidhya Nair, Xiao-Zheng Liu, Hieu S Vu, Lauren G Zacharias, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Jeffrey G McDonald, Andrew Lemoff, Yan Peng, Cheryl Lewis, Gonçalo Vale, Nils Halberg, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.
      Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.
    DOI:  https://doi.org/10.1038/s43018-023-00563-6
  15. Sci Adv. 2023 Jun 02. 9(22): eadh4251
    Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
    Scott A Jones, Prerana Gogoi, Jonathan J Ruprecht, Martin S King, Yang Lee, Thomas Zögg, Els Pardon, Deepak Chand, Stefan Steimle, Danielle M Copeman, Camila A Cotrim, Jan Steyaert, Paul G Crichton, Vera Moiseenkova-Bell, Edmund R S Kunji.
      Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.
    DOI:  https://doi.org/10.1126/sciadv.adh4251
  16. Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2217869120
    Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis.
    Wei Li, Junjie Kou, Zhenxi Zhang, Haoyue Li, Li Li, Wenjing Du.
      T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Myc flox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumorigenicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.
    Keywords:  MYC; T cell lymphomas; glutamine metabolism; malic enzyme 2; redox homeostasis
    DOI:  https://doi.org/10.1073/pnas.2217869120
  17. Cell Rep. 2023 May 30. pii: S2211-1247(23)00593-4. [Epub ahead of print]42(6): 112582
    Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
    Kelly Kersten, Ran You, Sophia Liang, Kevin M Tharp, Joshua Pollack, Valerie M Weaver, Matthew F Krummel, Mark B Headley.
      Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
    Keywords:  CP: Cancer; CP: Metabolism; infinity flow; lung; macrophages; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112582
  18. Methods Mol Biol. 2023 ;2675 297-308
    Spatial Analysis of Nucleotide Metabolism: From CRISPR Knockout Cancer Cells to MALDI Imaging of Tumors.
    Petra Hyrossova, Mirko Milosevic, Ahmad Y Alghadi, Lukas Kucera, Jan Prochazka, Radislav Sedlacek, Jakub Rohlena, Katerina Rohlenova.
      Cancer cells depend on nucleotides for proliferation. Inhibition of nucleotide metabolism by antimetabolites is a well-established anticancer therapy. However, resistance and toxicity to antimetabolite treatments reduce their effectiveness. Here, we focus on the pyrimidine de novo synthesis pathway, which is crucial for cancer cell proliferation, yet its pharmacological targeting in cancer has been without much clinical success so far. Hence, it is important to understand how cancer cells cope with the insufficiency of this pathway. Here, we describe a procedure to prepare subcutaneous tumor model deficient in de novo pyrimidine synthesis. For examination of metabolic responses to de novo synthesis blockade in tumors, we propose application of MALDI imaging that allows spatially resolved examination of metabolic responses to de novo synthesis blockade in tumors.
    Keywords:  CRISPR/Cas9; Cancer; MALDI; Metabolism; Nucleotides; Pyrimidines
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_22
  19. Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00589-2. [Epub ahead of print]42(6): 112578
    Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.
    Sinthu Pathmanapan, Raymond Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh A Seesankar, Adrian Kwan Ho Loe, Hongyuan H Zhang, Joan J Guinovart, Jordi Duran, Christopher B Newgard, Jay S Wunder, Benjamin A Alman.
      Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.
    Keywords:  CP: Cancer; CP: Metabolism; cancer; chondrosarcoma; development; genetic mutation; glycogen; metabolism; mutant IDH
    DOI:  https://doi.org/10.1016/j.celrep.2023.112578
  20. Methods Mol Biol. 2023 ;2675 149-165
    Real-Time Monitoring of Hydrogen Peroxide Levels in Yeast and Mammalian Cells.
    Gaetano Calabrese, Lianne J H C Jacobs, Jan Riemer.
      Hydrogen peroxide (H2O2) is an important signaling molecule involved in regulating antioxidative transcriptional responses, cellular differentiation, and hypoxia response. H2O2 generation and signaling are highly localized processes. Understanding the dynamics of this molecule inside intact cells with subcompartmental resolution is instrumental to unravel its role in cellular signaling. Different genetically encoded fluorescent sensors have been developed over the last few years that enable such non-disruptive monitoring with high spatiotemporal resolution. In this chapter, we describe the use of these genetically encoded sensors to directly monitor H2O2 dynamics in yeast and cultured mammalian cells.
    Keywords:  H2O2; Human; HyPer7; Hydrogen peroxide; Intracellular; Measurement; Redox; Yeast; roGFP2
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_12
  21. Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00594-6. [Epub ahead of print]42(6): 112583
    Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.
    Enric Mocholi, Laura Russo, Keshav Gopal, Andrew G Ramstead, Sophia M Hochrein, Harmjan R Vos, Geert Geeven, Adeolu O Adegoke, Anna Hoekstra, Robert M van Es, Jose Ramos Pittol, Sebastian Vastert, Jared Rutter, Timothy Radstake, Jorg van Loosdregt, Celia Berkers, Michal Mokry, Colin C Anderson, Ryan M O'Connell, Martin Vaeth, John Ussher, Boudewijn M T Burgering, Paul J Coffer.
      Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.
    Keywords:  CP: Metabolism; T cell; citrate; epigenetics; epigenome remodeling; glucose metabolism; glycolysis; histone acetylation; nuclear metabolism; pyruvate; pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112583
  22. Cell Rep. 2023 May 31. pii: S2211-1247(23)00601-0. [Epub ahead of print]42(6): 112590
    The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming.
    Shogo Sato, Tomoaki Hishida, Kenichiro Kinouchi, Fumiaki Hatanaka, Yumei Li, Quy Nguyen, Yumay Chen, Ping H Wang, Kai Kessenbrock, Wei Li, Juan Carlos Izpisua Belmonte, Paolo Sassone-Corsi.
      Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.
    Keywords:  CP: Stem cell research; Cryptochrome 1; circadian clock; iPSC reprogramming; metabolism; pluripotent stem cells; stem cell research; sterol regulatory element binding protein 1
    DOI:  https://doi.org/10.1016/j.celrep.2023.112590
  23. BMB Rep. 2023 May 31. pii: 5907. [Epub ahead of print]
    Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver.
    Milan Holeček.
      Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into cytosol in exchange with glutamate. The AGC2 is the main component of malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria. Through MAS, AGC2 is necessary for maintaining intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca2+ level, the AGC2 is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders. In these conditions, AGC2 increases aspartate input to the urea cycle, where aspartate is a source of one of two nitrogen atoms in the urea molecule (the next is ammonia) and a substrate for synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for synthesis of asparagine, nucleotides, and proteins. It is concluded that AGC2 has a fundamental role in compartmentalization of aspartate and glutamate metabolism and linking the reactions of MAS, glycolysis, gluconeogenesis, amino acid catabolism, urea cycle, protein synthesis, and cell proliferation. Targeting of AGC genes may represent a new therapeutic strategy to fight cancer.
  24. Sci Adv. 2023 Jun 02. 9(22): eadg4993
    ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation.
    Mengshu Jia, Xiao Yue, Weixia Sun, Qianjun Zhou, Cheng Chang, Weihua Gong, Jian Feng, Xie Li, Ruonan Zhan, Kemin Mo, Lijuan Zhang, Yajie Qian, Yuying Sun, Aoxue Wang, Yejun Zou, Weicai Chen, Yan Li, Li Huang, Yi Yang, Yuzheng Zhao, Xiawei Cheng.
      Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these processes is poorly understood. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is activated upon UNC-51-like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients are scarce and promotes lactate production. Lactate connects autophagy and glycolysis through Vps34 lactylation (at lysine-356 and lysine-781), which is mediated by the acyltransferase KAT5/TIP60. Vps34 lactylation enhances the association of Vps34 with Beclin1, Atg14L, and UVRAG, and then increases Vps34 lipid kinase activity. Vps34 lactylation promotes autophagic flux and endolysosomal trafficking. Vps34 lactylation in skeletal muscle during intense exercise maintains muscle cell homeostasis and correlates with cancer progress by inducing cell autophagy. Together, our findings describe autophagy regulation mechanism and then integrate cell autophagy and glycolysis.
    DOI:  https://doi.org/10.1126/sciadv.adg4993
  25. EMBO Rep. 2023 May 30. e56214
    Ovol1/2 loss-induced epidermal defects elicit skin immune activation and alter global metabolism.
    Morgan Dragan, Zeyu Chen, Yumei Li, Johnny Le, Peng Sun, Daniel Haensel, Suhas Sureshchandra, Anh Pham, Eddie Lu, Katherine Thanh Pham, Amandine Verlande, Remy Vu, Guadalupe Gutierrez, Wei Li, Cholsoon Jang, Selma Masri, Xing Dai.
      Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole-body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor-encoding Ovol1 and Ovol2 in adult epidermis results in barrier dysregulation through impacting epithelial-mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long-term consequences of epidermal-specific Ovol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole-body metabolism that is in part mediated through aberrant immune activation.
    Keywords:  Ovol1/Ovol2; epidermis; epithelial-mesenchymal plasticity (EMP); immune; metabolism
    DOI:  https://doi.org/10.15252/embr.202256214
  26. Methods Mol Biol. 2023 ;2675 51-63
    Quantification and Tracing of Stable Isotope into Cysteine and Glutathione.
    Yun Pyo Kang, Gina M DeNicola.
      The analysis of metabolic perturbation in biological samples is crucial to understand mechanisms of metabolic diseases. Here, we describe a protocol for quantitative stable isotope-labeled metabolite tracing of cysteine metabolism in cultured cells. This protocol relies on an extraction protocol to derivatize free thiols to prevent oxidation. In addition, the quantitative tracing of serine into multiple pathways, including the glutathione synthesis pathway, allows for the interrogation of cysteine and glutathione synthesis. This protocol provides a flexible framework that can be adapted to interrogate many metabolites and pathways of interest.
    Keywords:  Cell culture; Cysteine; Mass spectrometry; Quantification; Serine; Stable isotope standard; Stable isotope tracing
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_5
  27. Elife. 2023 Jun 01. pii: e84508. [Epub ahead of print]12
    The CD73 immune checkpoint promotes tumor cell metabolic fitness.
    David Allard, Isabelle Cousineau, Eric H Ma, Bertrand Allard, Yacine Bareche, Hubert Fleury, John Stagg.
      CD73 is an ectonucleotidase overexpressed on tumor cells that suppresses anti-tumor immunity. Accordingly, several CD73 inhibitors are currently being evaluated in the clinic, including in large randomized clinical trials. Yet, the tumor cell-intrinsic impact of CD73 remain largely uncharacterized. Using metabolomics, we discovered that CD73 significantly enhances tumor cell mitochondrial respiration and aspartate biosynthesis. Importantly, rescuing aspartate biosynthesis was sufficient to restore proliferation of CD73-deficient tumors in immune deficient mice. Seahorse analysis of a large panel of mouse and human tumor cells demonstrated that CD73 enhanced oxidative phosphorylation (OXPHOS) and glycolytic reserve. Targeting CD73 decreased tumor cell metabolic fitness, increased genomic instability and suppressed poly ADP ribose polymerase (PARP) activity. Our study thus uncovered an important immune-independent function for CD73 in promoting tumor cell metabolism, and provides the rationale for previously unforeseen combination therapies incorporating CD73 inhibition.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.84508
  28. Front Mol Biosci. 2023 ;10 1203269
    Emerging field: O-GlcNAcylation in ferroptosis.
    Hongshuo Zhang, Juan Zhang, Haojie Dong, Ying Kong, Youfei Guan.
      In 2012, researchers proposed a non-apoptotic, iron-dependent form of cell death caused by lipid peroxidation called ferroptosis. During the past decade, a comprehensive understanding of ferroptosis has emerged. Ferroptosis is closely associated with the tumor microenvironment, cancer, immunity, aging, and tissue damage. Its mechanism is precisely regulated at the epigenetic, transcriptional, and post-translational levels. O-GlcNAc modification (O-GlcNAcylation) is one of the post-translational modifications of proteins. Cells can modulate cell survival in response to stress stimuli, including apoptosis, necrosis, and autophagy, through adaptive regulation by O-GlcNAcylation. However, the function and mechanism of these modifications in regulating ferroptosis are only beginning to be understood. Here, we review the relevant literature within the last 5 years and present the current understanding of the regulatory function of O-GlcNAcylation in ferroptosis and the potential mechanisms that may be involved, including antioxidant defense system-controlled reactive oxygen species biology, iron metabolism, and membrane lipid peroxidation metabolism. In addition to these three areas of ferroptosis research, we examine how changes in the morphology and function of subcellular organelles (e.g., mitochondria and endoplasmic reticulum) involved in O-GlcNAcylation may trigger and amplify ferroptosis. We have dissected the role of O-GlcNAcylation in regulating ferroptosis and hope that our introduction will provide a general framework for those interested in this field.
    Keywords:  O-GlcNAcylation; ROS biology; ferroptosis; iron metabolism; lipid peroxidation; subcellular organelle
    DOI:  https://doi.org/10.3389/fmolb.2023.1203269
  29. Nature. 2023 May 31.
    Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
    Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Böttcher, Alberto Vides, Carlos I Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y Xue, Andreas Mantoulidis, Joachim Bröker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa de Stanchina, Ben Sang, Chuanchuan Li, Darryl B McConnell, Norbert Kraut, Piro Lito.
      KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.
    DOI:  https://doi.org/10.1038/s41586-023-06123-3
  30. Endocrinology. 2023 May 30. pii: bqad086. [Epub ahead of print]
    Circadian Regulation of Metabolism - Commitment to Health and Diseases.
    Tomoki Sato, Shogo Sato.
      The circadian clock is a biological time-keeping system to govern temporal rhythms of the endocrine system and metabolism. The master pacemaker of biological rhythms is housed in the hypothalamic suprachiasmatic nucleus (SCN) where approximately 20,000 neurons exist and receive light stimulus as a predominant timed external cue (zeitgeber). The central SCN clock orchestrates molecular clock rhythms in peripheral tissues and coordinates circadian metabolic homeostasis at a systemic level. Accumulated evidence underscores an intertwined relationship between the circadian clock system and metabolism: the circadian clock provides daily dynamics of metabolic activity whereas the circadian clock activity is modulated by metabolic and epigenetic mechanisms. Disruption of circadian rhythms due to shift work and jet lag confounds the daily metabolic cycle, thereby increasing risks of various metabolic diseases, such as obesity and type 2 diabetes (T2D). Food intake serves as a powerful zeitgeber to entrain molecular clocks and circadian clock regulation of metabolic pathways, independently of light exposure to the SCN. Thus, the daily timing of food intake rather than the diet quantity and quality contributes to promoting health and preventing disease development through restoring circadian control of metabolic pathways. In this review, we discuss how the circadian clock dominates metabolic homeostasis and how chrono-nutritional strategies benefit metabolic health, summarizing the latest evidence from basic and translational studies.
    Keywords:  Circadian clock; chrono-nutrition; gut microbiome; metabolic diseases; metabolism; multi-tissue communication
    DOI:  https://doi.org/10.1210/endocr/bqad086
  31. Cell. 2023 May 23. pii: S0092-8674(23)00522-6. [Epub ahead of print]
    Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.
    Deguang Liang, Yan Feng, Fereshteh Zandkarimi, Hua Wang, Zeda Zhang, Jinnie Kim, Yanyan Cai, Wei Gu, Brent R Stockwell, Xuejun Jiang.
      Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.
    Keywords:  MBOAT1; MBOAT2; androgen receptor; estrogen receptor; ferroptosis; phospholipid remodeling; sex hormone signaling
    DOI:  https://doi.org/10.1016/j.cell.2023.05.003
  32. Methods Mol Biol. 2023 ;2675 181-194
    13C Isotope Labeling and Mass Spectrometric Isotope Enrichment Analysis in Acute Brain Slices.
    Elisa Motori, Patrick Giavalisco.
      Feeding of stable 13C-labeled compounds coupled to mass spectrometric analysis has enabled the characterization of dynamic metabolite partitioning in various experimental conditions. This information is particularly relevant for the study and functional understanding of brain metabolic heterogeneity. We here describe a protocol for the analysis of metabolic enrichment analysis upon feeding of murine acute cerebellar slices with 13C-labeled substrates.
    Keywords:  13C labeling; Brain slices; Cellular metabolism; Cerebellum; Isotope enrichment; Liquid chromatography; Mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_14
  33. Mol Cell. 2023 Jun 01. pii: S1097-2765(23)00368-4. [Epub ahead of print]83(11): 1765-1766
    An unexpected pathway to polyamines in pancreatic cancer.
    Dominik Awad, Costas A Lyssiotis.
      In most adult tissues, arginine is the precursor to polyamines, poly-cationic metabolites that interact with negatively charged biomolecules like DNA. Lee et al.1 discovered that pancreatic cancers synthesize polyamines from glutamine, illuminating a new pathway and underscoring their metabolic flexibility.
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.014
  34. FEBS Lett. 2023 May 29.
    Cytochrome c oxidase biogenesis - from translation to early assembly of the core subunit COX1.
    Sven Dennerlein, Peter Rehling, Ricarda Richter-Dennerlein.
      Mitochondria are the powerhouses of the cell as they produce the majority of ATP with their oxidative phosphorylation (OXPHOS) machinery. The OXPHOS system is composed of the F1 Fo ATP synthase and four mitochondrial respiratory chain complexes, the terminal enzyme of which is the cytochrome c oxidase (complex IV) that transfers electrons to oxygen, generating water. Complex IV comprises of 14 structural subunits of dual genetic origin: while the three core subunits are mitochondrial encoded, the remaining constituents are encoded by the nuclear genome. Hence, the assembly of complex IV requires the coordination of two spatially separated gene expression machinery. Recent efforts elucidated an increasing number of proteins involved in mitochondrial gene expression, which are linked to complex IV assembly. Additionally, several COX1 biogenesis factors have been intensively biochemically investigated and an increasing number of structural snapshots shed light on the organization of macromolecular complexes such as the mitoribosome or the cytochrome c oxidase. Here, we focus on COX1 translation regulation and highlight the advanced understanding of early steps during COX1 assembly and its link to mitochondrial translation regulation.
    Keywords:  COX1; OXPHOS; complex IV; cytochrome c oxidase; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.14671
  35. Trends Cell Biol. 2023 May 16. pii: S0962-8924(23)00078-8. [Epub ahead of print]
    Reversing pathological cell states: the road less travelled can extend the therapeutic horizon.
    Boris N Kholodenko, Walter Kolch, Oleksii S Rukhlenko.
      Acquisition of omics data advances at a formidable pace. Yet, our ability to utilize these data to control cell phenotypes and design interventions that reverse pathological states lags behind. Here, we posit that cell states are determined by core networks that control cell-wide networks. To steer cell fate decisions, core networks connecting genotype to phenotype must be reconstructed and understood. A recent method, cell state transition assessment and regulation (cSTAR), applies perturbation biology to quantify causal connections and mechanistically models how core networks influence cell phenotypes. cSTAR models are akin to digital cell twins enabling us to purposefully convert pathological states back to physiologically normal states. While this capability has a range of applications, here we discuss reverting oncogenic transformation.
    Keywords:  cell state transition assessment and regulation method; control of cell state transitions and fate decisions; digital cell twins; omics data
    DOI:  https://doi.org/10.1016/j.tcb.2023.04.004
  36. Nat Commun. 2023 Jun 02. 14(1): 3192
    Lipid droplets are a metabolic vulnerability in melanoma.
    Dianne Lumaquin-Yin, Emily Montal, Eleanor Johns, Arianna Baggiolini, Ting-Hsiang Huang, Yilun Ma, Charlotte LaPlante, Shruthy Suresh, Lorenz Studer, Richard M White.
      Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
    DOI:  https://doi.org/10.1038/s41467-023-38831-9
  37. J Clin Invest. 2023 Jun 01. pii: e170195. [Epub ahead of print]133(11):
    Reporting on FH-deficient renal cell carcinoma using circulating succinylated metabolites.
    Divya Bezwada, James Brugarolas.
      Fumarate hydratase-deficient (FH-deficient) renal cell carcinoma (RCC) represents a particularly aggressive form of kidney cancer. FH-deficient RCC arises in the setting of germline, or solely somatic, mutations in the FH gene, a two-hit tumor suppressor gene. Early detection can be curative, but there are no biomarkers, and in the sporadic setting, establishing a diagnosis of FH-deficient RCC is challenging. In this issue of the JCI, Zheng, Zhu, and co-authors report untargeted plasma metabolomic analyses to identify putative biomarkers. They discovered two plasma metabolites directly linked to fumarate overproduction by tumor cells, succinyl-adenosine and succinic-cysteine, which correlate with tumor burden. The identification of circulating biomarkers of FH-deficient RCC may aid in the diagnosis of FH-deficient RCC and provide a means for longitudinal follow-up.
    DOI:  https://doi.org/10.1172/JCI170195
  38. Cell Chem Biol. 2023 May 22. pii: S2451-9456(23)00127-7. [Epub ahead of print]
    MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.
    Macarena Rodríguez-Prados, Kai-Ting Huang, Katalin Márta, Melanie Paillard, György Csordás, Suresh K Joseph, György Hajnóczky.
      Mitochondrial Ca2+ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca2+ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca2+-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharmacological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn2+-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU agonists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts.
    Keywords:  MCU; MICU1; Ru265; SB202190; calcium; kaempferol; ruthenium red; spermine
    DOI:  https://doi.org/10.1016/j.chembiol.2023.05.002
  39. Mol Cell. 2023 Jun 01. pii: S1097-2765(23)00332-5. [Epub ahead of print]83(11): 1903-1920.e12
    Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α.
    Mu A, Thomas E Wales, Haixia Zhou, Sorin-Valeriu Draga-Coletă, Christoph Gorgulla, Katherine A Blackmore, Melanie J Mittenbühler, Caroline R Kim, Dina Bogoslavski, Qiuyang Zhang, Zi-Fu Wang, Mark P Jedrychowski, Hyuk-Soo Seo, Kijun Song, Andrew Z Xu, Luke Sebastian, Steven P Gygi, Haribabu Arthanari, Sirano Dhe-Paganon, Patrick R Griffin, John R Engen, Bruce M Spiegelman.
      Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that the extracellular heat shock protein 90α (eHsp90α) is secreted by muscle with exercise and activates integrin αVβ5. This allows for high-affinity irisin binding and signaling through an Hsp90α/αV/β5 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 Å RMSD irisin/αVβ5 complex docking model. Irisin binds very tightly to an alternative interface on αVβ5 distinct from that used by known ligands. These data elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through an integrin receptor.
    Keywords:  HDX-MS; RGD motif; exercise; extracellular Hsp90; fibronectin III domain; integrin; integrin activation; irisin; ligand binding; protein-protein docking
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.008
  40. Nature. 2023 May 31.
    Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
    Avishai Gavish, Michael Tyler, Alissa C Greenwald, Rouven Hoefflin, Dor Simkin, Roi Tschernichovsky, Noam Galili Darnell, Einav Somech, Chaya Barbolin, Tomer Antman, Daniel Kovarsky, Thomas Barrett, L Nicolas Gonzalez Castro, Debdatta Halder, Rony Chanoch-Myers, Julie Laffy, Michael Mints, Adi Wider, Rotem Tal, Avishay Spitzer, Toshiro Hara, Maria Raitses-Gurevich, Chani Stossel, Talia Golan, Amit Tirosh, Mario L Suvà, Sidharth V Puram, Itay Tirosh.
      Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.
    DOI:  https://doi.org/10.1038/s41586-023-06130-4
  41. Nature. 2023 May 31.
    Deterministic evolution and stringent selection during preneoplasia.
    Kasper Karlsson, Moritz J Przybilla, Eran Kotler, Aziz Khan, Hang Xu, Kremena Karagyozova, Alexandra Sockell, Wing H Wong, Katherine Liu, Amanda Mah, Yuan-Hung Lo, Bingxin Lu, Kathleen E Houlahan, Zhicheng Ma, Carlos J Suarez, Chris P Barnes, Calvin J Kuo, Christina Curtis.
      The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.
    DOI:  https://doi.org/10.1038/s41586-023-06102-8
  42. Front Nutr. 2023 ;10 1124678
    A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition.
    Florian Lengauer, Franz Geisslinger, Antje Gabriel, Karin von Schwarzenberg, Angelika M Vollmar, Karin Bartel.
      It is widely known that most cancer cells display an increased reliance on glutaminolysis to sustain proliferation and survival. Combining glutamine deprivation with additional anti-cancer therapies is an intensively investigated approach to increase therapeutic effectiveness. In this study, we examined a combination of glutamine deprivation by starvation or pharmacological tools, with the anti-cancer agent archazolid, an inhibitor of the lysosomal V-ATPase. We show that glutamine deprivation leads to lysosomal acidification and induction of pro-survival autophagy, which could be prevented by archazolid. Surprisingly, a combination of glutamine deprivation with archazolid did not lead to synergistic induction of cell death or reduction in proliferation. Investigating the underlying mechanisms revealed elevated expression and activity of amino acid transporters SLC1A5, SLC38A1 upon starvation, whereas archazolid had no additional effect. Furthermore, we found that the export of lysosomal glutamine derived from exogenous sources plays no role in the phenotype as knock-down of SLC38A7, the lysosomal glutamine exporter, could not increase V-ATPase inhibition-induced cell death or reduce proliferation. Analysis of the cellular metabolic phenotype revealed that glutamine deprivation led to a significant increase in glycolytic activity, indicated by an elevated glycolytic capacity and reserve, when V-ATPase function was inhibited concomitantly. This was confirmed by increased glutamine uptake, augmented lactate production, and an increase in hexokinase activity. Our study, therefore, provides evidence, that glutamine deprivation induces autophagy, which can be prevented by simultaneous inhibition of V-ATPase function. However, this does not lead to a therapeutic benefit, as cells are able to circumvent cell death and growth inhibition by a metabolic shift toward glycolysis.
    Keywords:  V-ATPase; cancer; cancer metabolism; glutamine; glycolysis
    DOI:  https://doi.org/10.3389/fnut.2023.1124678
  43. Geroscience. 2023 May 31.
    A metabolomic signature of decelerated physiological aging in human plasma.
    Georges E Janssens, Lotte Grevendonk, Bauke V Schomakers, Ruben Zapata Perez, Michel van Weeghel, Patrick Schrauwen, Joris Hoeks, Riekelt H Houtkooper.
      The degenerative processes that occur during aging increase the risk of disease and impaired health. Meanwhile, interventions that target aging to promote healthy longevity are gaining interest, both academically and in the public. While nutritional and physical interventions exist, efficacy is often difficult to determine. It is therefore imperative that an aging score measuring the biological aging process is available to the wider public. However, simple, interpret, and accessible biological aging scores are lacking. Here, we developed PhysiAge, a physiological aging score based on five accessible parameters that have influence on or reflect the aging process: (1) average daily step count, (2) blood glucose, (3) systolic blood pressure, (4) sex, and (5) age. Here, we found that compared to calendar age alone, PhysiAge better predicts mortality, as well as established muscle aging markers such as decrease in NAD+ levels, increase in oxidative stress, and decline in physical functioning. In order to demonstrate the usefulness of PhysiAge in identifying relevant factors associated with decelerated aging, we calculated PhysiAges for a cohort of aged individuals and obtained mass spectrometry-based blood plasma metabolomic profiles for each individual. Here, we identified a metabolic signature of decelerated aging, which included components of the TCA cycle, including malate, citrate, and isocitrate. Higher abundance of these metabolites was associated with decelerated aging, in line with supplementation studies in model organisms. PhysiAge represents an accessible way for people to track and intervene in their aging trajectories, and identifies a metabolic signature of decelerated aging in human blood plasma, which can be further studied for its causal involvement in human aging.
    Keywords:  Aging clock; Aging interventions; Citrate; Healthy longevity; Isocitrate; Malate; Metabolomics; PhysiAge; Physiological aging; TCA cycle
    DOI:  https://doi.org/10.1007/s11357-023-00827-0
  44. Blood. 2023 May 30. pii: blood.2022018303. [Epub ahead of print]
    Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis.
    Sevgi Kostel Bal, Sarah Giuliani, Jana Block, Peter Repiscak, Christoph Hafemeister, Tala Shahin, Nurhan Kasap, Bernhard Ransmayr, Yirun Miao, Cheryl van de Wetering, Alexandra Frohne, Raul Jimenez-Heredia, Michael K Schuster, Samaneh Zoghi, Vanessa Hertlein, Marini Thian, Aleksandr Bykov, Royala Babayeva, Sevgi Bilgic Eltan, Elif Karakoc-Aydiner, Lisa E Shaw, Iftekhar Chowdury, Markku Varjosalo, Rafael Jose Argüello, Matthias Farlik, Ahmet Ozen, Edgar Albert Ernst Serfling, Loïc Dupré, Christoph Bock, Florian Halbritter, J Thomas Hannich, Irinka Castanon, Michael J Kraakman, Safa Baris, Kaan Boztug.
      The NFAT family of transcription factors plays central roles in adaptive immunity in murine models, however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified three patients carrying germline biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia and decreased antibody responses. The compound heterozygous NFATC1 variants identified in the patients caused decreased stability and reduced binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to reconstitution upon genetic rescue. Following stimulation, T-cell activation and proliferation were impaired, reaching that of healthy controls with delay indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells, revealed that NFATc1-dysfunction rendered T cells unable to engage in glycolysis following stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost activation responses. Indeed, we observed increased 13C-labelled palmitate incorporation into citrate indicating higher fatty acid oxidation and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, and reveal evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells to remedy delayed effector responses.
    DOI:  https://doi.org/10.1182/blood.2022018303
  45. Nat Commun. 2023 Jun 02. 14(1): 3187
    M1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development.
    Gabriela Poliacikova, Marine Barthez, Thomas Rival, Aïcha Aouane, Nuno Miguel Luis, Fabrice Richard, Fabrice Daian, Nicolas Brouilly, Frank Schnorrer, Corinne Maurel-Zaffran, Yacine Graba, Andrew J Saurin.
      Oxidative metabolism is the predominant energy source for aerobic muscle contraction in adult animals. How the cellular and molecular components that support aerobic muscle physiology are put in place during development through their transcriptional regulation is not well understood. Using the Drosophila flight muscle model, we show that the formation of mitochondria cristae harbouring the respiratory chain is concomitant with a large-scale transcriptional upregulation of genes linked with oxidative phosphorylation (OXPHOS) during specific stages of flight muscle development. We further demonstrate using high-resolution imaging, transcriptomic and biochemical analyses that Motif-1-binding protein (M1BP) transcriptionally regulates the expression of genes encoding critical components for OXPHOS complex assembly and integrity. In the absence of M1BP function, the quantity of assembled mitochondrial respiratory complexes is reduced and OXPHOS proteins aggregate in the mitochondrial matrix, triggering a strong protein quality control response. This results in isolation of the aggregate from the rest of the matrix by multiple layers of the inner mitochondrial membrane, representing a previously undocumented mitochondrial stress response mechanism. Together, this study provides mechanistic insight into the transcriptional regulation of oxidative metabolism during Drosophila development and identifies M1BP as a critical player in this process.
    DOI:  https://doi.org/10.1038/s41467-023-38986-5
  46. Cancer Cell. 2023 May 26. pii: S1535-6108(23)00172-1. [Epub ahead of print]
    Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
    Scott Haston, Estela Gonzalez-Gualda, Samir Morsli, Jianfeng Ge, Virinder Reen, Alexander Calderwood, Ilias Moutsopoulos, Leonidas Panousopoulos, Polina Deletic, Gabriela Carreno, Romain Guiho, Saba Manshaei, Jose Mario Gonzalez-Meljem, Hui Yuan Lim, Daniel J Simpson, Jodie Birch, Husayn A Pallikonda, Tamir Chandra, David Macias, Gary J Doherty, Doris M Rassl, Robert C Rintoul, Massimo Signore, Irina Mohorianu, Arne N Akbar, Jesús Gil, Daniel Muñoz-Espín, Juan Pedro Martinez-Barbera.
      The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.
    Keywords:  ABT-737; NSCLC; aging; cancer; endothelial cells; immunosuppression; macrophages; p16INK4a; senescence; senolytic
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.004
  47. BMC Cancer. 2023 May 30. 23(1): 484
    Is metabolism the magic bullet for targeted cancer therapy?
    Marija Trajkovic-Arsic, Elavarasan Subramani.
      Altered cellular metabolism has long been recognized as a hallmark of cancer. Oncogenic signaling cascades induce metabolic rewiring that further supports tumorigenesis, therapy resistance and metastasis. In view of this, the Collection on 'Cancer Metabolism' highlights the current views and focus of research on personalized medicine approach to target metabolism for cancer therapy.
    DOI:  https://doi.org/10.1186/s12885-023-10999-9
  48. Elife. 2023 Jun 01. pii: e80854. [Epub ahead of print]12
    MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer.
    Changyu Zhu, Yadira M Soto-Feliciano, John P Morris, Chun-Hao Huang, Richard P Koche, Yu-Jui Ho, Ana Banito, Chun-Wei David Chen, Aditya Shroff, Sha Tian, Geulah Livshits, Chi-Chao Chen, Myles Fennell, Scott A Armstrong, C David Allis, Darjus F Tschaharganeh, Scott W Lowe.
      Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.
    Keywords:  cancer biology; genetics; genomics; human; mouse
    DOI:  https://doi.org/10.7554/eLife.80854
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