bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–02–09
forty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.
  2. The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
  3. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  4. Arginine: at the crossroads of nitrogen metabolism.
  5. A new player in the mammalian electron transport chain.
  6. THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.
  7. Translocation renal cell carcinoma says no to the Warburg effect.
  8. Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.
  9. Activating AMPK improves pathological phenotypes due to mtDNA depletion.
  10. An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
  11. Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
  12. SERPINA3C as a mediator of metabolic health in offspring.
  13. GUK1 activation is a metabolic liability in lung cancer.
  14. Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
  15. Rhodoquinone carries electrons in the mammalian electron transport chain.
  16. Spatially mapping the tumour immune microenvironments of non-small cell lung cancer.
  17. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  18. Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins.
  19. Metabolic Messengers: small extracellular vesicles.
  20. Flow, sense and divide.
  21. Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
  22. The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
  23. A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.
  24. Regulation of stem cell function by NAD.
  25. Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche.
  26. Omega-3 supplements slow biological ageing.
  27. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma.
  28. Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity.
  29. Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.
  30. CD38 mediates nicotinamide mononucleotide base exchange to yield nicotinic acid mononucleotide.
  31. Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
  32. Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.
  33. Aging directs the differential evolution of KRAS-driven lung adenocarcinoma.
  34. Regulating MYC translation in cancer.
  35. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
  36. Quantifying cell divisions along evolutionary lineages in cancer.
  37. SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO.
  38. A Drosophila holidic diet optimized for growth and development.
  39. Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.
  40. Integrated control of leukocyte compartments as a feature of adaptive physiology.
  41. Expanding the genetic code for site-specific lysine lactylation.
  42. Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.
  43. N-formylkynurenine but not kynurenine enters a nucleophile-scavenging branch of the immune-regulatory kynurenine pathway.
  44. A comprehensive spatio-cellular map of the human hypothalamus.
  45. Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
  46. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  47. Tumor "age" in early-onset colorectal cancer.
  48. RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.
  49. Defining hypoxia in cancer: A landmark evaluation of hypoxia gene expression signatures.
  1. Nat Metab. 2025 Feb 06.
    Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.
    Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M Cornejo, Toni K Choueiri, Birgitta A Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R Viswanathan.
      Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01218-9
  2. Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00005-1. [Epub ahead of print]37(2): 316-329
    The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
    Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis.
      Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.
    Keywords:  BCAA metabolism; BCAAs; MMA; aging; branched-chain amino acids; cancer metabolism; metabolic disorders; methylmalonic acid; methylmalonyl-CoA; propionate; propionyl-CoA
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.005
  3. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  4. EMBO J. 2025 Feb 07.
    Arginine: at the crossroads of nitrogen metabolism.
    Tak Shun Fung, Keun Woo Ryu, Craig B Thompson.
      L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.
    Keywords:  Arginine Deficiency; Arginine Metabolism; Metabolite Signaling; Mitochondria; Protein Synthesis
    DOI:  https://doi.org/10.1038/s44318-025-00379-3
  5. Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00494-7. [Epub ahead of print]37(2): 310-312
    A new player in the mammalian electron transport chain.
    Judy Hirst.
      In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.012
  6. J Biol Chem. 2025 Feb 04. pii: S0021-9258(25)00099-7. [Epub ahead of print] 108252
    THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.
    Ben Reddan, Eoin P Cummins.
      Every cell in the body is exposed to a certain level of CO2 and O2. Hypercapnia and hypoxia elicit stress signals to influence cellular metabolism and function. Both conditions exert profound yet distinct effects on metabolic pathways and mitochondrial dynamics, highlighting the need for cells to adapt to changes in the gaseous microenvironment. The interplay between hypercapnia and hypoxia signalling is key for dictating cellular homeostasis as microenvironmental CO2 and O2 levels are inextricably linked. Hypercapnia, characterized by elevated pCO₂, introduces metabolic adaptations within the aerobic metabolism pathways, affecting TCA cycle flux, lipid, and amino acid metabolism, OXPHOS and the ETC. Hypoxia, defined by reduced oxygen availability, necessitates a shift from OXPHOS to anaerobic glycolysis to sustain ATP production, a process orchestrated by the stabilisation of HIF-1α. Given that hypoxia and hypercapnia are present in both physiological and cancerous microenvironments, how might the coexistence of hypercapnia and hypoxia influence metabolic pathways and cellular function in physiological niches and the tumor microenvironment?
    DOI:  https://doi.org/10.1016/j.jbc.2025.108252
  7. Nat Metab. 2025 Feb 06.
    Translocation renal cell carcinoma says no to the Warburg effect.
    Xingxiu Pan, Valentin Cracan.
      
    DOI:  https://doi.org/10.1038/s42255-025-01216-x
  8. EMBO Rep. 2025 Feb 07.
    Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.
    Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton.
      Cancer driver mutations are defined by their high prevalence in cancers and presumed rarity in normal tissues. However, recent studies show that positive selection in normal epithelia can increase the prevalence of some cancer drivers. To determine their true cancer-driving potential, it is essential to evaluate how frequent these mutations are in normal tissues and what are their phenotypes. Here, we explore the bioavailability of somatic variants by quantifying age-related mutational burdens in normal human colonic epithelium using immunodetection in FFPE samples (N = 181 patients). Positive selection of variants of tumour suppressor genes PTEN and ARID1A associates with monoallelic gene loss as confirmed by CRISPR/Cas9 mutagenesis and changes in their downstream effectors. Comparison of the mutational burden in normal tissue and colorectal cancers allows quantification of cancer driver potency based on relative representation. Additionally, immune exclusion, a cancer hallmark feature, is observed within ARID1A-deficient clones in histologically normal tissue. The behaviour resulting from haploinsufficiency of PTEN and ARID1A demonstrates how somatic mosaicism of tumour suppressors arises and can predispose to cancer initiation.
    Keywords:  ARID1A; Clone Dynamics; Haploinsufficency; Normal Tissue; PTEN
    DOI:  https://doi.org/10.1038/s44319-025-00373-0
  9. FEBS J. 2025 Feb 07.
    Activating AMPK improves pathological phenotypes due to mtDNA depletion.
    Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.
      AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.
    Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ
    DOI:  https://doi.org/10.1111/febs.70006
  10. Nat Cell Biol. 2025 Jan 31.
    An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
    Michaela Oborská-Oplová, Alexander Gregor Geiger, Erich Michel, Purnima Klingauf-Nerurkar, Sven Dennerlein, Yury S Bykov, Simona Amodeo, André Schneider, Maya Schuldiner, Peter Rehling, Vikram Govind Panse.
      The correct sorting of nascent ribosomal proteins from the cytoplasm to the nucleus or to mitochondria for ribosome production poses a logistical challenge for cellular targeting pathways. Here we report the discovery of a conserved mitochondrial avoidance segment (MAS) within the cytosolic ribosomal protein uS5 that resolves an evolutionary lethal conflict between the nuclear and mitochondrial targeting machinery. MAS removal mistargets uS5 to the mitochondrial matrix and disrupts the assembly of the cytosolic ribosome. The resulting lethality can be rescued by impairing mitochondrial import. We show that MAS triages nuclear targeting by disabling a cryptic mitochondrial targeting activity within uS5 and thereby prevents fatal capture by mitochondria. Our findings identify MAS as an essential acquisition by the primordial eukaryote that reinforced organelle targeting fidelity while developing an endosymbiotic relationship with its mitochondrial progenitor.
    DOI:  https://doi.org/10.1038/s41556-024-01588-4
  11. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251316350
    Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
    Noelle Alexa Novales, Hadar Meyer, Yeynit Asraf, Maya Schuldiner, Catherine F Clarke.
      Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.
    Keywords:  ER-mitochondrial encounter structure; artificial tether; coenzyme Q; mitochondria
    DOI:  https://doi.org/10.1177/25152564251316350
  12. Nat Metab. 2025 Jan 31.
    SERPINA3C as a mediator of metabolic health in offspring.
    Bianca E Suur, Emma Börgeson.
      
    DOI:  https://doi.org/10.1038/s42255-024-01209-2
  13. Cell. 2025 Jan 28. pii: S0092-8674(25)00093-5. [Epub ahead of print]
    GUK1 activation is a metabolic liability in lung cancer.
    Jaime L Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M Gassaway, Christian W Johnson, Nicole Jones, Zongyu Li, Christian P Joschko, Toshio Fujino, Joao A Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V Sequist, Jessica J Lin, Nathalie Y R Agar, Steven P Gygi, Kevin M Haigis, Aaron N Hata, Marcia C Haigis.
      Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.
    Keywords:  ALK; GDP; GUK1; Ras signaling; anaplastic lymphoma kinase; cancer metabolism; guanylate kinase 1; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.cell.2025.01.024
  14. Nat Commun. 2025 Feb 07. 16(1): 1460
    Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
    Trever T Greene, Yeara Jo, Carolina Chiale, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zúñiga.
      Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
    DOI:  https://doi.org/10.1038/s41467-025-56603-5
  15. Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]
    Rhodoquinone carries electrons in the mammalian electron transport chain.
    Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.
      Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
    Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone
    DOI:  https://doi.org/10.1016/j.cell.2024.12.007
  16. Nat Commun. 2025 Feb 04. 16(1): 1345
    Spatially mapping the tumour immune microenvironments of non-small cell lung cancer.
    Lysanne Desharnais, Mark Sorin, Morteza Rezanejad, Bridget Liu, Elham Karimi, Aline Atallah, Anikka M Swaby, Miranda W Yu, Samuel Doré, Saskia Hartner, Benoit Fiset, Yuhong Wei, Baharak Kadang, Roni Rayes, Philippe Joubert, Sophie Camilleri-Broët, Pierre-Olivier Fiset, Daniela F Quail, Jonathan D Spicer, Logan A Walsh.
      Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype's unique immune architecture, ultimately enhancing patient outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-56546-x
  17. bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.
    DOI:  https://doi.org/10.1101/2025.01.20.633997
  18. Mol Cancer. 2025 Feb 03. 24(1): 40
    Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins.
    Maria Angelica Freitas-Cortez, Fatemeh Masrorpour, Hong Jiang, Iqbal Mahmud, Yue Lu, Ailing Huang, Lisa K Duong, Qi Wang, Tiffany A Voss, Claudia S Kettlun Leyton, Bo Wei, Wai-Kin Chan, Kevin Lin, Jie Zhang, Efrosini Tsouko, Shonik Ganjoo, Hampartsoum B Barsoumian, Thomas S Riad, Yun Hu, Carola Leuschner, Nahum Puebla-Osorio, Jing Wang, Jian Hu, Michael A Davies, Vinay K Puduvalli, Cyrielle Billon, Thomas P Burris, Philip L Lorenzi, Boyi Gan, James W Welsh.
       BACKGROUND: Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7).
    METHODS: To explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8+ T cells, Cd8 cre;Rorafl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8+ T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry.
    RESULTS: PD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8+ T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy.
    CONCLUSIONS: Our study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis.
    Keywords:  Bmal1; Cancer; Circadian clock; FABP7; Ferroptosis; Immunotherapy; Lpcat3
    DOI:  https://doi.org/10.1186/s12943-024-02198-2
  19. Nat Metab. 2025 Feb 07.
    Metabolic Messengers: small extracellular vesicles.
    Theresa V Rohm, Karina Cunha E Rocha, Jerrold M Olefsky.
      Small extracellular vesicles (sEVs) are signalling molecules and biomarkers of cell status that govern a complex intraorgan and interorgan communication system through their cargo. Initially recognized as a waste disposal mechanism, they have emerged as important metabolic regulators. They transfer biological signals to recipient cells through their cargo content, and microRNAs (miRNAs) often mediate their metabolic effects. This review provides a concise overview of sEVs, specifically in the context of obesity-associated chronic inflammation and related metabolic disorders, describing their role as metabolic messengers, identifying their key sites of action and elucidating their mechanisms. We highlight studies that have shaped our understanding of sEV metabolism, address critical questions for future exploration, discuss the use of miRNAs as disease biomarkers and provide insights into the therapeutic potential of sEVs or specific miRNAs for treating metabolic diseases and related disorders in the future.
    DOI:  https://doi.org/10.1038/s42255-024-01214-5
  20. Nat Cell Biol. 2025 Jan 31.
    Flow, sense and divide.
    Nicoletta I Petridou.
      
    DOI:  https://doi.org/10.1038/s41556-024-01591-9
  21. Cancer Lett. 2025 Feb 01. pii: S0304-3835(25)00076-X. [Epub ahead of print] 217512
    Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
    Elena Richiardone, Maria Virginia Giolito, Rim Al Roumi, Jérôme Ambroise, Romain Boidot, Bernhard Drotleff, Bart Ghesquière, Barbara Lupo, Livio Trusolino, Alberto Bardelli, Sabrina Arena, Olivier Feron, Cyril Corbet.
      Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.
    Keywords:  Colon cancer; PHGDH; acidosis; metabolism; microenvironment; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.canlet.2025.217512
  22. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9
    The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
    Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.
      Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
    Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
  23. Nat Commun. 2025 Feb 03. 16(1): 1070
    A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.
    Zhen Zeng, Tianbei Zhang, Jiajia Zhang, Shuai Li, Sydney Connor, Boyang Zhang, Yimin Zhao, Jordan Wilson, Dipika Singh, Rima Kulikauskas, Candice D Church, Thomas H Pulliam, Saumya Jani, Paul Nghiem, Suzanne L Topalian, Patrick M Forde, Drew M Pardoll, Hongkai Ji, Kellie N Smith.
      Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.
    DOI:  https://doi.org/10.1038/s41467-024-55059-3
  24. Physiology (Bethesda). 2025 Feb 05.
    Regulation of stem cell function by NAD.
    Yufan Feng, Huixian Qiu, Danica Chen.
      
    Keywords:  NAD+; aging; sirtuin; stem cells
    DOI:  https://doi.org/10.1152/physiol.00052.2024
  25. Nat Commun. 2025 Feb 05. 16(1): 1378
    Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche.
    Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T Huse, Filippo G Giancotti.
      Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress response T cells in lungs from female mice harboring Brd7-deficient metastases. Finally, attenuating this immunosuppressive milieu by neutrophil depletion, neutrophil extracellular trap (NET) inhibition, or immune checkpoint therapy abrogates metastatic outgrowth. These findings implicate Brd7 and PBAF in triggering metastatic outgrowth in cancer, pointing to targetable underlying mechanisms involving specific immune cell compartments.
    DOI:  https://doi.org/10.1038/s41467-025-56347-2
  26. Nature. 2025 Feb 03.
    Omega-3 supplements slow biological ageing.
    Felicity Nelson.
      
    Keywords:  Ageing; Epigenetics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-00355-1
  27. Nature. 2025 Feb 05.
    A neoantigen vaccine generates antitumour immunity in renal cell carcinoma.
    David A Braun, Giorgia Moranzoni, Vipheaviny Chea, Bradley A McGregor, Eryn Blass, Chloe R Tu, Allison P Vanasse, Cleo Forman, Juliet Forman, Alexander B Afeyan, Nicholas R Schindler, Yiwen Liu, Shuqiang Li, Jackson Southard, Steven L Chang, Michelle S Hirsch, Nicole R LeBoeuf, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Susan Klaeger, Siranush Sarkizova, Christina B Pedersen, Matthew Mossanen, Isabel Carulli, Anna Tarren, Joseph Duke-Cohan, Alexis A Howard, J Bryan Iorgulescu, Bohoon Shim, Jeremy M Simon, Sabina Signoretti, Jon C Aster, Liudmila Elagina, Steven A Carr, Ignaty Leshchiner, Gad Getz, Stacey Gabriel, Nir Hacohen, Lars R Olsen, Giacomo Oliveira, Donna S Neuberg, Kenneth J Livak, Sachet A Shukla, Edward F Fritsch, Catherine J Wu, Derin B Keskin, Patrick A Ott, Toni K Choueiri.
      Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.
    DOI:  https://doi.org/10.1038/s41586-024-08507-5
  28. Nat Cell Biol. 2025 Feb 04.
    Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity.
    Joanna R Kovalski, Goksu Sarioglu, Vishvak Subramanyam, Grace Hernandez, Gilles Rademaker, Juan A Oses-Prieto, Macey Slota, Nimmy Mohan, Kaylee Yiakis, Isabelle Liu, Kwun Wah Wen, Grace E Kim, Sohit Miglani, Alma L Burlingame, Hani Goodarzi, Rushika M Perera, Davide Ruggero.
      Oncogenic protein dosage is tightly regulated to enable cancer formation but how this is regulated by translational control remains unknown. The Myc oncogene is a paradigm of an exquisitely regulated oncogene and a driver of pancreatic ductal adenocarcinoma (PDAC). Here we use a CRISPR interference screen in PDAC cells to identify activators of selective MYC translation. The top hit, the RNA-binding protein RBM42, is highly expressed in PDAC and predicts poor survival. We show that RBM42 binds and selectively regulates the translation of MYC and a precise suite of pro-oncogenic transcripts, including JUN and EGFR. Mechanistically, we find that RBM42 binds and remodels the MYC 5' untranslated region structure, facilitating the formation of the translation pre-initiation complex. Importantly, RBM42 is necessary for PDAC tumorigenesis in a Myc-dependent manner in vivo. This work transforms the understanding of the translational code in cancer and illuminates therapeutic openings to target the expression of oncogenes.
    DOI:  https://doi.org/10.1038/s41556-024-01604-7
  29. EMBO Rep. 2025 Jan 31.
    Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.
    Akshaya Seshadri, Anjana Badrinarayanan.
      Mitochondrial DNA (mtDNA) replication is essential for mitochondrial function. This is carried out by a dedicated DNA polymerase gamma, with 5'-3' polymerase and 3'-5' proofreading/ exonuclease activity. Perturbations to either property can have pathological consequences. Predominant sources for replication stress are DNA lesions, such as those induced by oxidative damage. How mtDNA lesions affect the polymerase activity and mtDNA stability in vivo is not fully understood. To address this, we induce mtDNA-specific damage in S. cerevisiae. We observe that mtDNA damage results in significant mtDNA loss. This loss occurs independent of cell cycle progression or cell division, suggesting an active mechanism for damaged mtDNA clearance. We implicate the 3'-5' exonuclease activity of the mtDNA polymerase in this clearance, with rates of loss being affected by cellular dNTP levels. Overall, our findings reveal context-dependent, selective regulation of two critical but opposing functions of polymerase gamma to ensure mitochondrial genome integrity.
    Keywords:  DNA Replication; Mip1; PolG; Proofreading; mtDNA Damage
    DOI:  https://doi.org/10.1038/s44319-025-00380-1
  30. J Biol Chem. 2025 Jan 31. pii: S0021-9258(25)00095-X. [Epub ahead of print] 108248
    CD38 mediates nicotinamide mononucleotide base exchange to yield nicotinic acid mononucleotide.
    Romanthi Madawala, Jasmine L Banks, Sarah E Hancock, Lake-Ee Quek, Nigel Turner, Lindsay E Wu.
      Nicotinamide mononucleotide (NMN) is a widely investigated metabolic precursor to the prominent enzyme cofactor nicotinamide adenine dinucleotide (NAD+), where it is assumed that delivery of this compound results in its direct incorporation into NAD+ via the canonical salvage / recycling pathway. Surprisingly, treatment with this salvage pathway intermediate leads to increases in nicotinic acid mononucleotide (NaMN) and nicotinic acid adenine dinucleotide (NaAD), two members of the Preiss-Handler / de novo pathways. In mammals, these pathways are not known to intersect prior to the production of NAD+. Here, we show that the cell surface enzyme CD38 can mediate a base exchange reaction on NMN, whereby the nicotinamide ring is exchanged with a free nicotinic acid to yield the Preiss-Handler / de novo pathway intermediate NaMN, with in vivo small molecule inhibition of CD38 abolishing the NMN-induced increase in NaMN and NaAD. Together, these data demonstrate a new mechanism by which the salvage pathway and Preiss-Handler / de novo pathways can exchange intermediates in mammalian NAD+ biosynthesis.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108248
  31. Signal Transduct Target Ther. 2025 Feb 07. 10(1): 36
    Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
    Fabian den Brave, Swadha Mishra, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s41392-025-02130-0
  32. Nat Commun. 2025 Jan 31. 16(1): 1217
    Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.
    Mengzhu Sun, Laure Garnier, Romane Chevalier, Martin Roumain, Chen Wang, Julien Angelillo, Julien Montorfani, Robert Pick, Dale Brighouse, Nadine Fournier, David Tarussio, Stéphanie Tissot, Jean-Marc Lobaccaro, Tatiana V Petrova, Camilla Jandus, Daniel E Speiser, Manfred Kopf, Caroline Pot, Christoph Scheiermann, Krisztian Homicsko, Giulio G Muccioli, Abhishek D Garg, Stéphanie Hugues.
      In melanoma, lymphangiogenesis correlates with metastasis and poor prognosis and promotes immunosuppression. However, it also potentiates immunotherapy by supporting immune cell trafficking. We show in a lymphangiogenic murine melanoma that lymphatic endothelial cells (LECs) upregulate the enzyme Ch25h, which catalyzes the formation of 25-hydroxycholesterol (25-HC) from cholesterol and plays important roles in lipid metabolism, gene regulation, and immune activation. We identify a role for LECs as a source of extracellular 25-HC in tumors inhibiting PPAR-γ in intra-tumoral macrophages and monocytes, preventing their immunosuppressive function and instead promoting their conversion into proinflammatory myeloid cells that support effector T cell functions. In human melanoma, LECs also upregulate Ch25h, and its expression correlates with the lymphatic vessel signature, infiltration of pro-inflammatory macrophages, better patient survival, and better response to immunotherapy. We identify here in mechanistic detail an important LEC function that supports anti-tumor immunity, which can be therapeutically exploited in combination with immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-55969-w
  33. bioRxiv. 2025 Jan 24. pii: 2025.01.20.633951. [Epub ahead of print]
    Aging directs the differential evolution of KRAS-driven lung adenocarcinoma.
    Felicia Lazure, Stanislav Drapela, Xiaoxian Liu, John H Lockhart, Hossein Kashfi, Nadir Sarigul, Didem Ilter, Elsa R Flores, Xuefeng Wang, Inna Smalley, Alex Jaeger, Xiaoqing Yu, Ana P Gomes.
      Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer( 1, 2 ), is a disease of the elderly, with an average age of diagnosis of about 70 years of age( 3 ). Older age is associated with an increased incidence of KRAS-driven LUAD( 4 ), a particularly deadly type of LUAD characterized by treatment resistance and relapse. Despite this, our understanding of how old age shapes KRAS-driven LUAD evolution remains incomplete. While the age-related increase in cancer risk was previously ascribed to the accumulation of mutations over time, we are now beginning to consider the role of host biology as an independent factor influencing cancer. Here, we use single-cell RNA-Sequencing of KP (Kras G12D/+ ; Trp53 flox/flox ) LUAD transplanted into young and old mice to define how old age affects LUAD evolution and map the changes that old age imposes onto LUAD's microenvironment. Our data demonstrates that the aged lung environment steers LUAD evolution towards a primitive stem-like state that is associated with poor prognosis. We ascribe this differential evolution, at least in part, to a population of rare and highly secretory damage-associated alveolar differentiation intermediate (ADI) cells that accumulate in the aged tumor microenvironment (TME) and that dominate the niche signaling received by LUAD cells. Overall, our data puts aging center stage in coordinating LUAD evolution, highlighting the need to model LUAD in its most common context and creating a framework to tailor future cancer therapeutic strategies to the age of the patient to improve outcomes in the largest and most vulnerable LUAD patient population, the elderly.
    DOI:  https://doi.org/10.1101/2025.01.20.633951
  34. Nat Cell Biol. 2025 Feb 07.
    Regulating MYC translation in cancer.
    Zainab Hussain, Mara H Sherman.
      
    DOI:  https://doi.org/10.1038/s41556-024-01589-3
  35. Nat Commun. 2025 Feb 06. 16(1): 1406
    ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
    Shiyang Wang, Xi Wu, Wenxin Bi, Jiuzhi Xu, Liyuan Hou, Guilin Li, Yuwei Pan, Hanfu Zhang, Mengzhen Li, Sujuan Du, Mingxin Zhang, Di Liu, Shuiling Jin, Xiaojing Shi, Yuhua Tian, Jianwei Shuai, Maksim V Plikus, Moshi Song, Zhaocai Zhou, Lu Yu, Cong Lv, Zhengquan Yu.
      Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-56444-2
  36. Nat Genet. 2025 Feb 04.
    Quantifying cell divisions along evolutionary lineages in cancer.
    Martin Blohmer, David M Cheek, Wei-Ting Hung, Maria Kessler, Foivos Chatzidimitriou, Jiahe Wang, William Hung, I-Hsiu Lee, Alexander N Gorelick, Emma Ce Wassenaar, Ching-Yeuh Yang, Yi-Chen Yeh, Hsiang-Ling Ho, Dorothee Speiser, Maria M Karsten, Michael Lanuti, Sara I Pai, Onno Kranenburg, Jochen K Lennerz, Teh-Ying Chou, Matthias Kloor, Kamila Naxerova.
      Cell division drives somatic evolution but is challenging to quantify. We developed a framework to count cell divisions with DNA replication-related mutations in polyguanine homopolymers. Analyzing 505 samples from 37 patients, we studied the milestones of colorectal cancer evolution. Primary tumors diversify at ~250 divisions from the founder cell, while distant metastasis divergence occurs significantly later, at ~500 divisions. Notably, distant but not lymph node metastases originate from primary tumor regions that have undergone surplus divisions, tying subclonal expansion to metastatic capacity. Then, we analyzed a cohort of 73 multifocal lung cancers and showed that the cell division burden of the tumors' common ancestor distinguishes independent primary tumors from intrapulmonary metastases and correlates with patient survival. In lung cancer too, metastatic capacity is tied to more extensive proliferation. The cell division history of human cancers is easily accessible using our simple framework and contains valuable biological and clinical information.
    DOI:  https://doi.org/10.1038/s41588-025-02078-5
  37. Nature. 2025 Feb 05.
    SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO.
    Patricia C Borck, Isabella Boyle, Kristina Jankovic, Nolan Bick, Kyla Foster, Anthony C Lau, Lucy I Parker-Burns, Daniel A Lubicki, Tianxia Li, Ashir A Borah, Nicholas J Lofaso, Sohani Das Sharma, Tessla Chan, Riya V Kishen, Anisah Adeagbo, Srivatsan Raghavan, Elisa Aquilanti, John R Prensner, J Michael Krill-Burger, Todd R Golub, Catarina D Campbell, Joshua M Dempster, Edmond M Chan, Francisca Vazquez.
      Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach1-3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO, for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.
    DOI:  https://doi.org/10.1038/s41586-024-08509-3
  38. Dev Cell. 2025 Feb 03. pii: S1534-5807(25)00028-0. [Epub ahead of print]
    A Drosophila holidic diet optimized for growth and development.
    Sebastian Sorge, Victor Girard, Lena Lampe, Vanessa Tixier, Alexandra Weaver, Theresa Higgins, Alex P Gould.
      Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organism Drosophila melanogaster, existing holidic diets are unable to support the rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimization strategy across more than 50 diet variants to design a holidic diet for fast development (HolFast), a holidic medium tailored for fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimized. Rapid development on HolFast is not improved by adding fatty acids, but it is dependent upon their de novo synthesis in the fat body via fatty acid synthase (FASN). HolFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HolFast has wide applications in nutritional and metabolic studies of Drosophila development.
    Keywords:  Drosophila larval development; amino acids; chemically defined diet; holidic diet; lipid metabolism; microbiota; nutrition; vitamins
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.008
  39. iScience. 2025 Feb 21. 28(2): 111731
    Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.
    Shuyuan Chang, Ayaka Tomii, Yunfei Zhou, Xun Yang, Yihong Dong, Jun Yan, Aodi Wu, Yumeng Wang, Qingxin Zhang, Hongxue Meng, Lei Yu, Wei Sun, Dabin Liu.
      Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo, highlighting its potential therapeutic applications.
    Keywords:  Biological sciences; Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111731
  40. Immunity. 2025 Feb 04. pii: S1074-7613(25)00038-X. [Epub ahead of print]
    Integrated control of leukocyte compartments as a feature of adaptive physiology.
    Nikolai P Jaschke, Andrew Wang.
      As a highly diverse and mobile organ, the immune system is uniquely equipped to participate in tissue responses in a tunable manner, depending on the number, type, and nature of cells deployed to the respective organ. Most acute organismal stressors that threaten survival-predation, infection, poisoning, and others-induce pronounced redistribution of immune cells across tissue compartments. Here, we review the current understanding of leukocyte compartmentalization under homeostatic and noxious conditions. We argue that leukocyte shuttling between compartments is a function of local tissue demands, which are linked to the organ's contribution to adaptive physiology at steady state and upon challenge. We highlight the neuroendocrine signals that relay and organize this trafficking behavior and outline mechanisms underlying the functional diversification of leukocyte responses. In this context, we discuss important areas of future inquiry and the implications of this scientific space for clinical medicine in the era of targeted immunomodulation.
    Keywords:  adaptive physiology; interorgan crosstalk; leukocyte compartments; leukocyte trafficking; neuroendocrinology; neutrophils
    DOI:  https://doi.org/10.1016/j.immuni.2025.01.013
  41. Nat Rev Mol Cell Biol. 2025 Feb 04.
    Expanding the genetic code for site-specific lysine lactylation.
    Zhi Zong.
      
    DOI:  https://doi.org/10.1038/s41580-025-00832-5
  42. bioRxiv. 2025 Jan 22. pii: 2025.01.22.634160. [Epub ahead of print]
    Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.
    Dantong Zhu, Judy Z Wu, Patrick Griffin, Brady A Samuelson, David A Sinclair, Alice E Kane.
      Frailty is an age-related geriatric syndrome, for which the mechanisms remain largely unknown. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma samples. We identify differentially abundant metabolites related to aging, determine frailty related metabolites via a machine learning approach, and generate a union set of frailty features, both in the whole cohort and in sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan, and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. In summary, our results identify sex-specific metabolite biomarkers of frailty in aging, and shed light on potential mechanisms involved in frailty.
    DOI:  https://doi.org/10.1101/2025.01.22.634160
  43. Bioorg Chem. 2025 Jan 28. pii: S0045-2068(25)00099-9. [Epub ahead of print]156 108219
    N-formylkynurenine but not kynurenine enters a nucleophile-scavenging branch of the immune-regulatory kynurenine pathway.
    Yongxin Wang, Euphemia Leung, Petr Tomek.
      Tryptophan catabolism along the kynurenine pathway (KP) mediates key physiological functions ranging from immune tolerance to lens UV protection, but the contributory roles and chemical fates of individual KP metabolites are incompletely understood. This particularly concerns the first KP metabolite, N-formylkynurenine (NFK), canonically viewed as a transient precursor to the downstream kynurenine (KYN). Here, we challenge that canon and show that hydrolytic enzymes act as a rheostat switching NFK's fate between the canonical KP and a novel non-enzymatic branch of tryptophan catabolism. In the physiological environment (37 °C, pH 7.4), NFK deaminated into electrophilic NFK-carboxyketoalkene (NFK-CKA), which rapidly (<2 min) formed adducts with nucleophiles such as cysteine and glutathione, the key intracellular antioxidants. Serum hydrolases suppressed NFK deamination as they hydrolysed NFK to KYN ∼3 times faster than NFK deaminates. Whilst KYN did not deaminate, its deaminated product (KYN-CKA) rapidly reacted with cysteine but not glutathione. The new NFK transformations of a yet to be discovered function highlight NFK's significance beyond hydrolysis to KYN and suggests the dominance of its chemical transformations over those of KYN. Enzyme compartmentalisation and abundance offer insights into the regulation of non-enzymatic KP metabolite transformations such as KYN involved in immune regulation, protein modification, lens aging or neuropathology.
    Keywords:  Carboxyketoalkene; Deamination; Formylkynurenine; Hydrolysis; Kynurenine; Thiol; Tryptophan catabolism
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108219
  44. Nature. 2025 Feb 05.
    A comprehensive spatio-cellular map of the human hypothalamus.
    John A Tadross, Lukas Steuernagel, Georgina K C Dowsett, Katherine A Kentistou, Sofia Lundh, Marta Porniece, Paul Klemm, Kara Rainbow, Henning Hvid, Katarzyna Kania, Joseph Polex-Wolf, Lotte Bjerre Knudsen, Charles Pyke, John R B Perry, Brian Y H Lam, Jens C Brüning, Giles S H Yeo.
      The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions1. However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies2,3. Here we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the 'HYPOMAP'. Although conservation of neuronal cell types between humans and mice, as based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments. Out of the 452 hypothalamic cell types, we find that 291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 'effector' genes. Rare deleterious variants in six of these (MC4R, PCSK1, POMC, CALCR, BSN and CORO1A) associate with BMI at population level, and CORO1A has not been linked previously to BMI. Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify new druggable targets for treating a wide range of conditions, including reproductive, circadian and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41586-024-08504-8
  45. Aging Dis. 2025 Feb 01.
    Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
    Runyu Liang, Qiang Tang, Jia Chen, Yongyin Huang, Luwen Zhu.
      Since the association between mitochondria and aging was first identified, significant efforts have been devoted to elucidating the role of mitochondrial DNA mutations in the aging process. Due to their age-dependent accumulation, intrinsically high mutation rates, and defective replication mechanisms, mtDNA mutations have often been regarded as pivotal drivers of aging. This has led to certain intuitive yet inherently limited conclusions. Aging, however, is a multifactorial process, and the role of mtDNA cannot be simply categorized in binary terms, as its influence emerges as a composite vector of numerous interconnected physiological processes. Adopting alternative perspectives may mitigate the discrepancies between theoretical expectations and empirical findings, offering new directions and insights for future research.
    DOI:  https://doi.org/10.14336/AD.2024.1469
  46. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  47. Cell. 2025 Feb 06. pii: S0092-8674(24)01416-8. [Epub ahead of print]188(3): 589-593
    Tumor "age" in early-onset colorectal cancer.
    Gianluca Mauri, Giorgio Patelli, Giovanni Crisafulli, Salvatore Siena, Alberto Bardelli.
      The incidence of early-onset colorectal cancer (EO-CRC) is surging, and by 2030, one-third of all CRCs will occur before the commonly recommended screening age of 50 years. The time required for EO-CRC to reach the metastatic stage is unknown, yet this knowledge is critical to tailor early-diagnosis screening strategies. Here, we discuss how defining a key biological feature of EO-CRC may be central to protecting young adults from an alarming and probably unprecedented tumor epidemic.
    DOI:  https://doi.org/10.1016/j.cell.2024.12.003
  48. Nature. 2025 Feb 05.
    RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.
    Yinshan Fang, Sanny S W Chung, Le Xu, Chenyi Xue, Xue Liu, Dianhua Jiang, Rongbo Li, Yohei Korogi, Ke Yuan, Anjali Saqi, Hanina Hibshoosh, Yuefeng Huang, Chyuan-Sheng Lin, Tatsuya Tsukui, Dean Sheppard, Xin Sun, Jianwen Que.
      A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1-3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR+ fibroblasts that arise during alveologenesis include SCUBE2+ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1+POSTN+ pathological fibroblasts. Genetic ablation of POSTN+ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with LeprcreERT2 or Scube2creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR+ cells that include SCUBE2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.
    DOI:  https://doi.org/10.1038/s41586-024-08542-2
  49. Cell Genom. 2025 Jan 30. pii: S2666-979X(25)00020-5. [Epub ahead of print] 100764
    Defining hypoxia in cancer: A landmark evaluation of hypoxia gene expression signatures.
    Matteo Di Giovannantonio, Fiona Hartley, Badran Elshenawy, Alessandro Barberis, Dan Hudson, Hana S Shafique, Vincent E S Allott, David A Harris, Simon R Lord, Syed Haider, Adrian L Harris, Francesca M Buffa, Benjamin H L Harris.
      Tumor hypoxia drives metabolic shifts, cancer progression, and therapeutic resistance. Challenges in quantifying hypoxia have hindered the exploitation of this potential "Achilles' heel." While gene expression signatures have shown promise as surrogate measures of hypoxia, signature usage is heterogeneous and debated. Here, we present a systematic pan-cancer evaluation of 70 hypoxia signatures and 14 summary scores in 104 cell lines and 5,407 tumor samples using 472 million length-matched random gene signatures. Signature and score choice strongly influenced the prediction of hypoxia in vitro and in vivo. In cell lines, the Tardon signature was highly accurate in both bulk and single-cell data (94% accuracy, interquartile mean). In tumors, the Buffa and Ragnum signatures demonstrated superior performance, with Buffa/mean and Ragnum/interquartile mean emerging as the most promising for prospective clinical trials. This work delivers recommendations for experimental hypoxia detection and patient stratification for hypoxia-targeting therapies, alongside a generalizable framework for signature evaluation.
    Keywords:  biomarkers; gene signature; hypoxia; hypoxia-targeting therapies; patient stratification; radiotherapy; signature scores; single cell; transcriptomics; tumorigenesis
    DOI:  https://doi.org/10.1016/j.xgen.2025.100764
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