bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–09–08
58 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
  2. Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
  3. Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.
  4. A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.
  5. F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
  6. Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.
  7. Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
  8. BioID-based intact cell interactome of the Kv1.3 potassium channel identifies a Kv1.3-STAT3-p53 cellular signaling pathway.
  9. Mechanisms that clear mutations drive field cancerization in mammary tissue.
  10. Mitochondrial transplants to treat mitochondrial dysfunction.
  11. Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
  12. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  13. Career pathways, part 15.
  14. MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer.
  15. mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
  16. Mapping the transcriptional evolution of human metastatic breast cancer.
  17. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
  18. Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut.
  19. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  20. Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors.
  21. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
  22. Skull bones harbour immune cells that are poised to target brain tumours.
  23. The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity.
  24. Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis.
  25. Citrullination modulation stabilizes HIF-1α to promote tumour progression.
  26. Integration of mass cytometry and mass spectrometry imaging for spatially resolved single-cell metabolic profiling.
  27. Micronuclear collapse from oxidative damage.
  28. Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
  29. Older age reduces mtDNA mutation inheritance.
  30. LIANA+ provides an all-in-one framework for cell-cell communication inference.
  31. Mapping cellular interactions from spatially resolved transcriptomics data.
  32. In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
  33. Recon8D: A metabolic regulome network from oct-omics and machine learning.
  34. Time-resolved NMR detection of prolyl-hydroxylation in intrinsically disordered region of HIF-1α.
  35. In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.
  36. Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes.
  37. H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.
  38. The crosstalk between metabolism and translation.
  39. Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer.
  40. Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.
  41. Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
  42. A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.
  43. DNA methylation controls stemness of astrocytes in health and ischaemia.
  44. Context-dependent impact of the dietary non-essential amino acid tyrosine on Drosophila physiology and longevity.
  45. A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.
  46. A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
  47. Measuring Entanglement in Physical Networks.
  48. Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
  49. Phospholipid scrambling induced by an ion channel/metabolite transporter complex.
  50. Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice.
  51. Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.
  52. GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.
  53. MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development.
  54. Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility.
  55. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.
  56. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
  57. Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.
  58. Multiplex genome editing eliminates the Warburg Effect without impacting growth rate in mammalian cells.
  1. FEBS Lett. 2024 Sep 03.
    Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
    Lishu Guo.
      The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
    Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition
    DOI:  https://doi.org/10.1002/1873-3468.15008
  2. Life Sci Alliance. 2024 Nov;pii: e202402764. [Epub ahead of print]7(11):
    Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
    Vanessa Xavier, Silvia Martinelli, Ryan Corbyn, Rachel Pennie, Kai Rakovic, Ian R Powley, Leah Officer-Jones, Vincenzo Ruscica, Alison Galloway, Leo M Carlin, Victoria H Cowling, John Le Quesne, Jean-Claude Martinou, Thomas MacVicar.
      Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.
    DOI:  https://doi.org/10.26508/lsa.202402764
  3. Nat Metab. 2024 Aug 29.
    Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.
    Nina Grankvist, Cecilia Jönsson, Karin Hedin, Nicolas Sundqvist, Per Sandström, Bergthor Björnsson, Arjana Begzati, Evgeniya Mickols, Per Artursson, Mohit Jain, Gunnar Cedersund, Roland Nilsson.
      Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global 13C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system.
    DOI:  https://doi.org/10.1038/s42255-024-01119-3
  4. Elife. 2024 Sep 03. pii: RP92707. [Epub ahead of print]12
    A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.
    Brennan J Wadsworth, Marina Leiwe, Eleanor A Minogue, Pedro P Cunha, Viktor Engman, Carolin Brombach, Christos Asvestis, Shiv K Sah-Teli, Emilia Marklund, Peppi Karppinen, Jorge L Ruas, Helene Rundqvist, Johanna T Lanner, Randall S Johnson.
      Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.
    Keywords:  Exercise; biochemistry; chemical biology; metabolite; mouse; muscle fiber
    DOI:  https://doi.org/10.7554/eLife.92707
  5. Pharmacol Res. 2024 Sep 02. pii: S1043-6618(24)00338-4. [Epub ahead of print]208 107393
    F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
    Lishu Guo.
      Mitochondria are metabolic hub, and act as primary sites for reactive oxygen species (ROS) and metabolites generation. Mitochondrial Ca2+ uptake contributes to Ca2+ storage. Mitochondria-organelle interactions are important for cellular metabolic adaptation, biosynthesis, redox balance, cell fate. Organelle communications are mediated by Ca2+/ROS signals, vesicle transport and membrane contact sites. The permeability transition pore (PTP) is an unselective channel that provides a release pathway for Ca2+/ROS, mtDNA and metabolites. F-ATP synthase inhibitory factor 1 (IF1) participates in regulation of PTP opening and is required for the translocation of transcriptional factors c-Myc/PGC1α to mitochondria to stimulate metabolic switch. IF1, a mitochondrial specific protein, has been suggested to regulate other organelles including nucleus, endoplasmic reticulum and lysosomes. IF1 may be able to mediate mitochondria-organelle interactions and cellular physiology through regulation of PTP activity.
    Keywords:  Ca(2+); F-ATP synthase inhibitory factor 1; Metabolites; Mitochondria; Mitochondria-organelle interactions; Permeability transition; ROS
    DOI:  https://doi.org/10.1016/j.phrs.2024.107393
  6. Science. 2024 Sep 06. 385(6713): eadk9217
    Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.
    Cancer Genome Atlas Analysis Network‡
      To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.
    DOI:  https://doi.org/10.1126/science.adk9217
  7. J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746
    Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
    Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.
      Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
    Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1016/j.jbc.2024.107746
  8. Sci Adv. 2024 Sep 06. 10(36): eadn9361
    BioID-based intact cell interactome of the Kv1.3 potassium channel identifies a Kv1.3-STAT3-p53 cellular signaling pathway.
    Elena Prosdocimi, Veronica Carpanese, Luca Matteo Todesca, Tatiana Varanita, Magdalena Bachmann, Margherita Festa, Daniele Bonesso, Mireia Perez-Verdaguer, Andrea Carrer, Angelo Velle, Roberta Peruzzo, Silvia Muccioli, Davide Doni, Luigi Leanza, Paola Costantini, Frank Stein, Mandy Rettel, Antonio Felipe, Michael J Edwards, Erich Gulbins, Laura Cendron, Chiara Romualdi, Vanessa Checchetto, Ildiko Szabo.
      Kv1.3 is a multifunctional potassium channel implicated in multiple pathologies, including cancer. However, how it is involved in disease progression is not fully clear. We interrogated the interactome of Kv1.3 in intact cells using BioID proximity labeling, revealing that Kv1.3 interacts with STAT3- and p53-linked pathways. To prove the relevance of Kv1.3 and of its interactome in the context of tumorigenesis, we generated stable melanoma clones, in which ablation of Kv1.3 remodeled gene expression, reduced proliferation and colony formation, yielded fourfold smaller tumors, and decreased metastasis in vivo in comparison to WT cells. Kv1.3 deletion or pharmacological inhibition of mitochondrial Kv1.3 increased mitochondrial Reactive Oxygen Species release, decreased STAT3 phosphorylation, stabilized the p53 tumor suppressor, promoted metabolic switch, and altered the expression of several BioID-identified Kv1.3-networking proteins in tumor tissues. Collectively, our work revealed the tumor-promoting Kv1.3-interactome landscape, thus opening the way to target Kv1.3 not only as an ion-conducting entity but also as a signaling hub.
    DOI:  https://doi.org/10.1126/sciadv.adn9361
  9. Nature. 2024 Sep;633(8028): 198-206
    Mechanisms that clear mutations drive field cancerization in mammary tissue.
    Grand Challenge PRECISION consortium
      Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1-3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1-/-;Trp53-/- cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.
    DOI:  https://doi.org/10.1038/s41586-024-07882-3
  10. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  11. Cell Metab. 2024 Sep 03. pii: S1550-4131(24)00330-9. [Epub ahead of print]36(9): 1911-1913
    Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
    Hee-Hoon Kim, Vishwa Deep Dixit.
      Organismal aging involves several hallmark pathways, including chronic inflammation and metabolic dysfunction. However, the origin of age-related inflammation is incompletely understood. In a recent study published in Nature,1 Widjaja et al. show that blocking the age-related increase in IL-11 restores immune-metabolic homeostasis and extends healthspan and lifespan in mice.
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.003
  12. Nat Metab. 2024 Sep 02.
    Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
    Ritsuko Nakai, Stella Varnum, Rachael L Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J Krysa, Eva F Cohen, Nicholas Borcherding, Russell P Saneto, Rick C Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R Brestoff.
      Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
    DOI:  https://doi.org/10.1038/s42255-024-01125-5
  13. Nat Metab. 2024 Sep 03.
    Career pathways, part 15.
    Marina Garcia-Macia, Fei Yin.
      
    DOI:  https://doi.org/10.1038/s42255-024-01122-8
  14. Gut. 2024 Aug 31. pii: gutjnl-2024-332350. [Epub ahead of print]
    MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer.
    Yingying Tang, Shijie Tang, Wenjuan Yang, Zhengyan Zhang, Teng Wang, Yuyun Wu, Junyi Xu, Christian Pilarsky, Massimiliano Mazzone, Lei-Wei Wang, Yongwei Sun, Ruijun Tian, Yujie Tang, Yu Wang, Chaochen Wang, Jing Xue.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC.
    DESIGN: To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice.
    RESULTS: Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy.
    CONCLUSION: In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.
    Keywords:  cancer immunobiology; cellular immunity; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2024-332350
  15. bioRxiv. 2024 Aug 07. pii: 2024.08.06.606942. [Epub ahead of print]
    mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
    Madison Lehmer, Roberto Zoncu.
      Lysosomes regulate mitochondrial function through multiple mechanisms including the master regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) protein kinase, which is activated at the lysosomal membrane by nutrient, growth factor and energy signals. mTORC1 promotes mitochondrial protein composition changes, respiratory capacity, and dynamics, though the full range of mitochondrial-regulating functions of this protein kinase remain undetermined. We find that acute chemical modulation of mTORC1 signaling decreased mitochondrial oxygen consumption, increased mitochondrial membrane potential and reduced susceptibility to stress-induced mitophagy. In cellular models of Friedreich's Ataxia (FA), where loss of the Frataxin (FXN) protein suppresses Fe-S cluster synthesis and mitochondrial respiration, the changes induced by mTORC1 inhibitors lead to improved cell survival. Proteomic-based profiling uncover compositional changes that could underlie mTORC1-dependent modulation of FXN-deficient mitochondria. These studies highlight mTORC1 signaling as a regulator of mitochondrial composition and function, prompting further evaluation of this pathway in the context of mitochondrial disease.
    DOI:  https://doi.org/10.1101/2024.08.06.606942
  16. J Clin Invest. 2024 Sep 03. pii: e183971. [Epub ahead of print]134(17):
    Mapping the transcriptional evolution of human metastatic breast cancer.
    Melissa Q Reeves.
      Many aspects of breast cancer metastasis remain poorly understood, despite its clinical importance. In this issue of the JCI, Winkler et al. have applied an elegant patient-derived xenograft (PDX) model to map the transcriptomes of single cells in matched primary tumors and lung metastases across 13 breast cancer PDX models. They identified distinct transcriptional changes associated with metastatic evolution in lowly and highly metastatic primary tumors. Furthermore, by classifying the "epithelial-mesenchymal plasticity" (EMP) state of single cells, they revealed that considerable EMP heterogeneity exists among primary and metastatic human breast cancer cells. However, the EMP profile of a tumor does not change substantially upon metastasis. These findings give an unprecedentedly detailed view into the transcriptional heterogeneity and evolution of metastatic human breast cancer.
    DOI:  https://doi.org/10.1172/JCI183971
  17. Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952
    SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
    Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.
      Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
    Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)
    DOI:  https://doi.org/10.1016/j.mito.2024.101952
  18. Cell Rep. 2024 Sep 04. pii: S2211-1247(24)01044-1. [Epub ahead of print]43(9): 114693
    Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut.
    Maximilian C Vonolfen, Fenja L Meyer Zu Altenschildesche, Hyuck-Jin Nam, Susanne Brodesser, Akos Gyenis, Jan Buellesbach, Geanette Lam, Carl S Thummel, Gilles Storelli.
      Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.
    Keywords:  CP: Metabolism; CP: Molecular biology; Drosophila; chylomicron; enterocyte; gut-liver axis; hepatocyte nuclear factor 4; inflammation; lipid; lipoprotein; metabolism; oenocyte
    DOI:  https://doi.org/10.1016/j.celrep.2024.114693
  19. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  20. Cancer Cell. 2024 Aug 28. pii: S1535-6108(24)00304-0. [Epub ahead of print]
    Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors.
    Itay Tirosh, Mario L Suva.
      Human tumors are intricate ecosystems composed of diverse genetic clones and malignant cell states that evolve in a complex tumor micro-environment. Single-cell RNA-sequencing (scRNA-seq) provides a compelling strategy to dissect this intricate biology and has enabled a revolution in our ability to understand tumor biology over the last ten years. Here we reflect on this first decade of scRNA-seq in human tumors and highlight some of the powerful insights gleaned from these studies. We first focus on computational approaches for robustly defining cancer cell states and their diversity and highlight some of the most common patterns of gene expression intra-tumor heterogeneity (eITH) observed across cancer types. We then discuss ambiguities in the field in defining and naming such eITH programs. Finally, we highlight critical developments that will facilitate future research and the broader implementation of these technologies in clinical settings.
    DOI:  https://doi.org/10.1016/j.ccell.2024.08.005
  21. Nat Commun. 2024 Sep 01. 15(1): 7609
    Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
    F Nadalin, M J Marzi, M Pirra Piscazzi, P Fuentes-Bravo, S Procaccia, M Climent, P Bonetti, C Rubolino, B Giuliani, I Papatheodorou, J C Marioni, F Nicassio.
      Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-51424-4
  22. Nature. 2024 Sep 03.
    Skull bones harbour immune cells that are poised to target brain tumours.
    Juyeun Lee, Justin D Lathia.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02789-5
  23. Nat Cell Biol. 2024 Sep 02.
    The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity.
    Kathryn Hockemeyer, Theodore Sakellaropoulos, Xufeng Chen, Olha Ivashkiv, Maria Sirenko, Hua Zhou, Giovanni Gambi, Elena Battistello, Kleopatra Avrampou, Zhengxi Sun, Maria Guillamot, Luis Chiriboga, George Jour, Igor Dolgalev, Kate Corrigan, Kamala Bhatt, Iman Osman, Aristotelis Tsirigos, Nikos Kourtis, Iannis Aifantis.
      Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.
    DOI:  https://doi.org/10.1038/s41556-024-01490-z
  24. Cancer Discov. 2024 Sep 04. 14(9): 1581-1583
    Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis.
    Christopher M Arends, Siddhartha Jaiswal.
      There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal hematopoiesis driver mutations to classify somatic mutations in blood for 12 genes in a purely data-driven way. See related article by Demajo et al., p. 1717 (9).
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0751
  25. Nat Commun. 2024 Sep 03. 15(1): 7654
    Citrullination modulation stabilizes HIF-1α to promote tumour progression.
    Rui Chen, Zhiyuan Lin, Shengqi Shen, Chuxu Zhu, Kai Yan, Caixia Suo, Rui Liu, Haoran Wei, Li Gao, Kaixiang Fan, Huafeng Zhang, Linchong Sun, Ping Gao.
      Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1αR698 citrullination blocks von Hippel-Lindau (VHL) binding, thereby antagonizing HIF-1α ubiquitination and subsequent proteasome degradation. We also show that citrullinated HIF-1αR698, HIF-1α and PADI4 are highly expressed in hepatocellular carcinoma (HCC) tumour tissues, suggesting a potential correlation between PADI4-mediated HIF-1αR698 citrullination and cancer development. Furthermore, we identify that dihydroergotamine mesylate (DHE) acts as an antagonist of PADI4, which ultimately suppresses tumour progression. Collectively, our results reveal citrullination as a posttranslational modification related to HIF-1α stability, and suggest that targeting PADI4-mediated HIF-1α citrullination is a promising therapeutic strategy for cancers with aberrant HIF-1α expression.
    DOI:  https://doi.org/10.1038/s41467-024-51882-w
  26. Nat Methods. 2024 Aug 29.
    Integration of mass cytometry and mass spectrometry imaging for spatially resolved single-cell metabolic profiling.
    Joana B Nunes, Marieke E Ijsselsteijn, Tamim Abdelaal, Rick Ursem, Manon van der Ploeg, Martin Giera, Bart Everts, Ahmed Mahfouz, Bram Heijs, Noel F C C de Miranda.
      The integration of spatial omics technologies can provide important insights into the biology of tissues. Here we combined mass spectrometry imaging-based metabolomics and imaging mass cytometry-based immunophenotyping on a single tissue section to reveal metabolic heterogeneity at single-cell resolution within tissues and its association with specific cell populations such as cancer cells or immune cells. This approach has the potential to greatly increase our understanding of tissue-level interplay between metabolic processes and their cellular components.
    DOI:  https://doi.org/10.1038/s41592-024-02392-6
  27. Science. 2024 Aug 30. 385(6712): eadj8691
    Micronuclear collapse from oxidative damage.
    Melody Di Bona, Yanyang Chen, Albert S Agustinus, Alice Mazzagatti, Mercedes A Duran, Matthew Deyell, Daniel Bronder, James Hickling, Christy Hong, Lorenzo Scipioni, Giulia Tedeschi, Sara Martin, Jun Li, Aušrinė Ruzgaitė, Nadeem Riaz, Parin Shah, Edridge K D'Souza, D Zack Brodtman, Simone Sidoli, Bill Diplas, Manisha Jalan, Nancy Y Lee, Alban Ordureau, Benjamin Izar, Ashley M Laughney, Simon Powell, Enrico Gratton, Stefano Santaguida, John Maciejowski, Peter Ly, Thomas M Jeitner, Samuel F Bakhoum.
      Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.
    DOI:  https://doi.org/10.1126/science.adj8691
  28. Nat Aging. 2024 Aug 29.
    Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
    Suchira Gallage, Elaine E Irvine, Jose Efren Barragan Avila, Virinder Reen, Silvia M A Pedroni, Imanol Duran, Vikas Ranvir, Sanjay Khadayate, Joaquim Pombo, Sharon Brookes, Danijela Heide, Gopuraja Dharmalingham, Agharul I Choudhury, Indrabahadur Singh, Nicolás Herranz, Santiago Vernia, Mathias Heikenwalder, Jesús Gil, Dominic J Withers.
      Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00695-z
  29. Nat Aging. 2024 Sep 04.
    Older age reduces mtDNA mutation inheritance.
    Polyxeni Papadea, Nils-Göran Larsson.
      
    DOI:  https://doi.org/10.1038/s43587-024-00701-4
  30. Nat Cell Biol. 2024 Sep 02.
    LIANA+ provides an all-in-one framework for cell-cell communication inference.
    Daniel Dimitrov, Philipp Sven Lars Schäfer, Elias Farr, Pablo Rodriguez-Mier, Sebastian Lobentanzer, Pau Badia-I-Mompel, Aurelien Dugourd, Jovan Tanevski, Ricardo Omar Ramirez Flores, Julio Saez-Rodriguez.
      The growing availability of single-cell and spatially resolved transcriptomics has led to the development of many approaches to infer cell-cell communication, each capturing only a partial view of the complex landscape of intercellular signalling. Here we present LIANA+, a scalable framework built around a rich knowledge base to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially resolved data. By extending and unifying established methodologies, LIANA+ provides a comprehensive set of synergistic components to study cell-cell communication via diverse molecular mediators, including those measured in multi-omics data. LIANA+ is accessible at https://github.com/saezlab/liana-py with extensive vignettes ( https://liana-py.readthedocs.io/ ) and provides an all-in-one solution to intercellular communication inference.
    DOI:  https://doi.org/10.1038/s41556-024-01469-w
  31. Nat Methods. 2024 Sep 03.
    Mapping cellular interactions from spatially resolved transcriptomics data.
    James Zhu, Yunguan Wang, Woo Yong Chang, Alicia Malewska, Fabiana Napolitano, Jeffrey C Gahan, Nisha Unni, Min Zhao, Rongqing Yuan, Fangjiang Wu, Lauren Yue, Lei Guo, Zhuo Zhao, Danny Z Chen, Raquibul Hannan, Siyuan Zhang, Guanghua Xiao, Ping Mu, Ariella B Hanker, Douglas Strand, Carlos L Arteaga, Neil Desai, Xinlei Wang, Yang Xie, Tao Wang.
      Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently through the introduction of spatially resolved transcriptomics (SRT) technologies, especially those that achieve single-cell resolution. Nevertheless, substantial challenges remain to analyze such highly complex data properly. Here, we introduce a multiple-instance learning framework, Spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight Spacia's power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates and, most importantly, the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of Spacia for three commercialized single-cell resolution SRT technologies: MERSCOPE/Vizgen, CosMx/NanoString and Xenium/10x. Overall, Spacia represents a notable step in advancing quantitative theories of cellular communications.
    DOI:  https://doi.org/10.1038/s41592-024-02408-1
  32. Science. 2024 Sep 06. 385(6713): 1086-1090
    In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
    Lea Dietrich, Ahmed-Noor A Agip, Christina Kunz, Andre Schwarz, Werner Kühlbrandt.
      Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate Polytomella by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F1 head. The Polytomella ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.
    DOI:  https://doi.org/10.1126/science.adp4640
  33. bioRxiv. 2024 Aug 19. pii: 2024.08.17.608400. [Epub ahead of print]
    Recon8D: A metabolic regulome network from oct-omics and machine learning.
    Ryan Schildcrout, Kirk Smith, Rupa Bhowmick, Suraj Menon, Minali Kapadia, Emily Kurtz, Anya Coffeen-Vandeven, Sriram Chandrasekaran.
      The complexity and incompleteness of metabolic-regulatory networks make it challenging to predict metabolomes from other omics. Using machine learning, we predicted metabolomic variation across ~1000 different cancer cell lines from matched oct-omics data: genomics, epigenomics (histone post-translational modifications (PTMs) and DNA-methylation), transcriptomics, RNA splicing, miRNA-omics, proteomics, and phosphoproteomics. Overall, the metabolome is tightly associated with the transcriptome, while miRNAs, phosphoproteins and histone PTMs have the highest metabolic information per feature. Metabolites in peripheral metabolism are predictable via levels of corresponding enzymes, while those in central metabolism require combinatorial predictors in signaling and redox pathways, and may not reflect corresponding pathway expression. We reconstruct multiomic interaction subnetworks for highly predictable metabolites, and YAP1 signaling emerged as a top global predictor across 4 omic layers. We prioritize predictive multiomic features for single-cell and spatial metabolomics assays. Top predictors were enriched for synthetic-lethal interactions and synergistic combination therapies that target compensatory metabolic modulators.
    DOI:  https://doi.org/10.1101/2024.08.17.608400
  34. Proc Natl Acad Sci U S A. 2024 Sep 10. 121(37): e2408104121
    Time-resolved NMR detection of prolyl-hydroxylation in intrinsically disordered region of HIF-1α.
    Wenguang He, Geneviève M C Gasmi-Seabrook, Mitsuhiko Ikura, Jeffrey E Lee, Michael Ohh.
      Prolyl-hydroxylation is an oxygen-dependent posttranslational modification (PTM) that is known to regulate fibril formation of collagenous proteins and modulate cellular expression of hypoxia-inducible factor (HIF) α subunits. However, our understanding of this important but relatively rare PTM has remained incomplete due to the lack of biophysical methodologies that can directly measure multiple prolyl-hydroxylation events within intrinsically disordered proteins. Here, we describe a real-time 13C-direct detection NMR-based assay for studying the hydroxylation of two evolutionarily conserved prolines (P402 and P564) simultaneously in the intrinsically disordered oxygen-dependent degradation domain of hypoxic-inducible factor 1α by exploiting the "proton-less" nature of prolines. We show unambiguously that P564 is rapidly hydroxylated in a time-resolved manner while P402 hydroxylation lags significantly behind that of P564. The differential hydroxylation rate was negligibly influenced by the binding affinity to prolyl-hydroxylase enzyme, but rather by the surrounding amino acid composition, particularly the conserved tyrosine residue at the +1 position to P564. These findings support the unanticipated notion that the evolutionarily conserved P402 seemingly has a minimal impact in normal oxygen-sensing pathway.
    Keywords:  13C-direct detection NMR; hypoxia-inducible factor; intrinsically disordered protein; prolyl-hydroxylation
    DOI:  https://doi.org/10.1073/pnas.2408104121
  35. Nat Genet. 2024 Sep 03.
    In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.
    Peiran Su, Yin Liu, Tianyi Chen, Yibo Xue, Yong Zeng, Guanghui Zhu, Sujun Chen, Mona Teng, Xinpei Ci, Mengdi Guo, Michael Y He, Jun Hao, Vivian Chu, Wenxi Xu, Shiyan Wang, Parinaz Mehdipour, Xin Xu, Sajid A Marhon, Fraser Soares, Nhu-An Pham, Bell Xi Wu, Peter Hyunwuk Her, Shengrui Feng, Najd Alshamlan, Maryam Khalil, Rehna Krishnan, Fangyou Yu, Chang Chen, Francis Burrows, Razqallah Hakem, Mathieu Lupien, Shane Harding, Benjamin H Lok, Catherine O'Brien, Alejandro Berlin, Daniel D De Carvalho, David G Brooks, Daniel Schramek, Ming-Sound Tsao, Housheng Hansen He.
      Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.
    DOI:  https://doi.org/10.1038/s41588-024-01874-9
  36. J Clin Invest. 2024 Sep 03. pii: e164227. [Epub ahead of print]134(17):
    Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes.
    Juliane Winkler, Weilun Tan, Catherine Mm Diadhiou, Christopher S McGinnis, Aamna Abbasi, Saad Hasnain, Sophia Durney, Elena Atamaniuc, Daphne Superville, Leena Awni, Joyce V Lee, Johanna H Hinrichs, Patrick S Wagner, Namrata Singh, Marco Y Hein, Michael Borja, Angela M Detweiler, Su-Yang Liu, Ankitha Nanjaraj, Vaishnavi Sitarama, Hope S Rugo, Norma Neff, Zev J Gartner, Angela Oliveira Pisco, Andrei Goga, Spyros Darmanis, Zena Werb.
      Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.
    Keywords:  Bioinformatics; Breast cancer; Oncology
    DOI:  https://doi.org/10.1172/JCI164227
  37. Cell Rep. 2024 Aug 30. pii: S2211-1247(24)01037-4. [Epub ahead of print]43(9): 114686
    H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.
    Ruijie Wang, Chuwen Li, Zhongyi Cheng, Mingyu Li, Jianbo Shi, Zhiyuan Zhang, Shufang Jin, Hailong Ma.
      Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ T cell exhaustion, and cholesterol-modified siIL11 restores CD8+ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.
    Keywords:  CP: Cancer; CP: Metabolism; T cell dysfunction; head and neck squamous cell carcinoma; histone lactylation; interleukin-11; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.114686
  38. Cell Metab. 2024 Sep 03. pii: S1550-4131(24)00324-3. [Epub ahead of print]36(9): 1945-1962
    The crosstalk between metabolism and translation.
    Stefano Biffo, Davide Ruggero, Massimo Mattia Santoro.
      Metabolism and mRNA translation represent critical steps involved in modulating gene expression and cellular physiology. Being the most energy-consuming process in the cell, mRNA translation is strictly linked to cellular metabolism and in synchrony with it. Indeed, several mRNAs for metabolic pathways are regulated at the translational level, resulting in translation being a coordinator of metabolism. On the other hand, there is a growing appreciation for how metabolism impacts several aspects of RNA biology. For example, metabolic pathways and metabolites directly control the selectivity and efficiency of the translational machinery, as well as post-transcriptional modifications of RNA to fine-tune protein synthesis. Consistently, alterations in the intricate interplay between translational control and cellular metabolism have emerged as a critical axis underlying human diseases. A better understanding of such events will foresee innovative therapeutic strategies in human disease states.
    Keywords:  disease; mRNA translation; metabolism; protein synthesis; signaling
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.022
  39. Cancer Cell. 2024 Aug 22. pii: S1535-6108(24)00296-4. [Epub ahead of print]
    Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer.
    Caitlin A McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G Aveson, David J Falvo, William B Fall, Christopher W Chan, Andrew Wenger, Brett L Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M O'Reilly, Shauna L Houlihan, Alicia Alonso, Erika Hissong, George M Church, Christopher E Mason, Despina Siolas, Faiyaz Notta, Mithat Gonen, Lukas E Dow, William R Jarnagin, Rohit Chandwani.
      KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.
    Keywords:  KRAS; clinical outcomes; genomics; organoids; pancreatic cancer; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.ccell.2024.08.002
  40. Nat Commun. 2024 Sep 05. 15(1): 7769
    Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.
    Augusto Faria Andrade, Alva Annett, Elham Karimi, Danai Georgia Topouza, Morteza Rezanejad, Yitong Liu, Michael McNicholas, Eduardo G Gonzalez Santiago, Dhana Llivichuzhca-Loja, Arne Gehlhaar, Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Caterina Russo, Damien Faury, Geoffroy Danieau, Evan Puligandla, Yuhong Wei, Michele Zeinieh, Qing Wu, Steven Hebert, Nikoleta Juretic, Emily M Nakada, Brian Krug, Valerie Larouche, Alexander G Weil, Roy W R Dudley, Jason Karamchandani, Sameer Agnihotri, Daniela F Quail, Benjamin Ellezam, Liza Konnikova, Logan A Walsh, Manav Pathania, Claudia L Kleinman, Nada Jabado.
      Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.
    DOI:  https://doi.org/10.1038/s41467-024-52096-w
  41. Autophagy. 2024 Sep 03. 1-3
    Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
    Hao Liu, Jianming Xie, Cien Zhen, Lin Zeng, Hualin Fan, Haixia Zhuang, Du Feng.
      Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.
    Keywords:  Autophagy; CGAS-STING1; LIR; TFAM; mitochondria DNA
    DOI:  https://doi.org/10.1080/15548627.2024.2395145
  42. Nat Cancer. 2024 Sep 03.
    A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.
    Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A Davies, Yiling Lu, Rehan Akbani, Gordon B Mills, Han Liang.
      The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43018-024-00817-x
  43. Nature. 2024 Sep 04.
    DNA methylation controls stemness of astrocytes in health and ischaemia.
    Lukas P M Kremer, Santiago Cerrizuela, Hadil El-Sammak, Mohammad Eid Al Shukairi, Tobias Ellinger, Jannes Straub, Aylin Korkmaz, Katrin Volk, Jan Brunken, Susanne Kleber, Simon Anders, Ana Martin-Villalba.
      Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells1-3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions4-6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes7. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-024-07898-9
  44. Sci Adv. 2024 Aug 30. 10(35): eadn7167
    Context-dependent impact of the dietary non-essential amino acid tyrosine on Drosophila physiology and longevity.
    Hina Kosakamoto, Chisako Sakuma, Rina Okada, Masayuki Miura, Fumiaki Obata.
      Dietary protein intake modulates growth, reproduction, and longevity by stimulating amino acid (AA)-sensing pathways. Essential AAs are often considered as limiting nutrients during protein scarcity, and the role of dietary non-essential AAs (NEAAs) is less explored. Although tyrosine has been reported to be crucial for sensing protein restriction in Drosophila larvae, its effect on adult physiology and longevity remains unclear. Here, using a synthetic diet, we perform a systematic investigation of the effect of single NEAA deprivation on nutrient-sensing pathways, reproductive ability, starvation resistance, feeding behavior, and life span in adult female flies. Specifically, dietary tyrosine deprivation decreases internal tyrosine levels and fecundity, influences AA-sensing machineries, and extends life span. These nutritional responses are not observed under higher total AA intake or in infertile female flies, suggesting a context-dependent influence of dietary tyrosine. Our findings highlight the unique role of tyrosine as a potentially limiting nutrient, underscoring its value for dietary interventions aimed at enhancing health span.
    DOI:  https://doi.org/10.1126/sciadv.adn7167
  45. Science. 2024 Aug 30. 385(6712): eadj7446
    A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.
    Sara Martin, Simone Scorzoni, Sara Cordone, Alice Mazzagatti, Galina V Beznoussenko, Amanda L Gunn, Melody Di Bona, Yonatan Eliezer, Gil Leor, Tal Ben-Yishay, Alessia Loffreda, Valeria Cancila, Maria Chiara Rainone, Marica Rosaria Ippolito, Valentino Martis, Fabio Bedin, Massimiliano Garrè, Laura Pontano Vaites, Paolo Vasapolli, Simona Polo, Dario Parazzoli, Claudio Tripodo, Alexander A Mironov, Alessandro Cuomo, Uri Ben-David, Samuel F Bakhoum, Emily M Hatch, Peter Ly, Stefano Santaguida.
      Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.
    DOI:  https://doi.org/10.1126/science.adj7446
  46. Autophagy. 2024 Aug 30.
    A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
    Sebastian J Hofer, Ioanna Daskalaki, Mahmoud Abdellatif, Ulrich Stelzl, Simon Sedej, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.
      Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.
    Keywords:  Aging; MTOR; autophagy; lifespan; rapamycin; spermidine
    DOI:  https://doi.org/10.1080/15548627.2024.2396793
  47. Phys Rev Lett. 2024 Aug 16. 133(7): 077401
    Measuring Entanglement in Physical Networks.
    Cory Glover, Albert-László Barabási.
      The links of a physical network cannot cross, which often forces the network layout into nonoptimal entangled states. Here we define a network fabric as a two-dimensional projection of a network and propose the average crossing number as a measure of network entanglement. We analytically derive the dependence of the average crossing number on network density, average link length, degree heterogeneity, and community structure and show that the predictions accurately estimate the entanglement of both network models and of real physical networks.
    DOI:  https://doi.org/10.1103/PhysRevLett.133.077401
  48. Cell. 2024 Aug 27. pii: S0092-8674(24)00895-X. [Epub ahead of print]
    Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
    Tao Long, Dongyu Li, Goncalo Vale, Yaoyukun Jiang, Philip Schmiege, Zhongyue J Yang, Jeffrey G McDonald, Xiaochun Li.
      In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1WT), the LMS-causing Pro269Ser mutant (PSS1P269S), and PSS1WT in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.
    Keywords:  DS55980254; LDL; LDL receptors; MBOAT; PSS1; cholesterol trafficking; phosphatidylserine
    DOI:  https://doi.org/10.1016/j.cell.2024.08.004
  49. Nat Commun. 2024 Aug 31. 15(1): 7566
    Phospholipid scrambling induced by an ion channel/metabolite transporter complex.
    Han Niu, Masahiro Maruoka, Yuki Noguchi, Hidetaka Kosako, Jun Suzuki.
      Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca2+) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca2+-activated K+ channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca2+ stimulation, along with Kcnn4 activation.
    DOI:  https://doi.org/10.1038/s41467-024-51939-w
  50. bioRxiv. 2024 Aug 19. pii: 2024.08.19.608291. [Epub ahead of print]
    Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice.
    Marte Molenaars, Hannan Mir, Samantha W Alvarez, Lakshmi Arivazhagan, Carolina Rosselot, Di Zhan, Christopher Y Park, Adolfo Garcia-Ocana, Ann Marie Schmidt, Richard Possemato.
      Iron-sulfur clusters (ISCs) are cell-essential cofactors present in ∼60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes.
    Graphical abstract:
    Highlights: Acute ISC inhibition leads to rapid loss of adiposity in miceMulti-metabolic pathway disruption upon ISC deficiency blocks energy storageNfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in β-cellsEnergy distress caused by inhibition of ISC synthesis is attenuated in aged mice.
    DOI:  https://doi.org/10.1101/2024.08.19.608291
  51. bioRxiv. 2024 Jul 31. pii: 2023.09.06.556606. [Epub ahead of print]
    Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.
    Preeti Yadav, Javier Gómez Ortega, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper Wang, Tatsuya Tsukui, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L Eckalbar, Ari B Molofsky, Paul J Wolters, Stanley J Tamaki, Trever Bivona, Adam R Abate, Allon Wagner, Kevin M Tharp, Mallar Bhattacharya.
      Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.
    DOI:  https://doi.org/10.1101/2023.09.06.556606
  52. Cancer Cell. 2024 Aug 27. pii: S1535-6108(24)00305-2. [Epub ahead of print]
    GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.
    Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca F Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia A Hack, Michael A Quezada, Valeria Molinari, McKenzie L Shaw, Marta Perez-Somarriba, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M Mire, Li Jiang, Andrezza Nascimento, Jenna LaBelle, Rebecca Haase, Jacob Rozowsky, Sina Neyazi, Alicia-Christina Baumgartner, Sophia Castellani, Samantha E Hoffman, Amy Cameron, Murry Morrow, Quang-De Nguyen, Giulia Pericoli, Sibylle Madlener, Lisa Mayr, Christian Dorfer, Rene Geyeregger, Christopher Rota, Gerda Ricken, Keith L Ligon, Sanda Alexandrescu, Rodrigo T Cartaxo, Benison Lau, Santhosh Uphadhyaya, Carl Koschmann, Emelie Braun, Miri Danan-Gotthold, Lijuan Hu, Kimberly Siletti, Erik Sundström, Rebecca Hodge, Ed Lein, Sameer Agnihotri, David D Eisenstat, Simon Stapleton, Andrew King, Cristina Bleil, Angela Mastronuzzi, Kristina A Cole, Angela J Waanders, Angel Montero Carcaboso, Ulrich Schüller, Darren Hargrave, Maria Vinci, Fernando Carceller, Christine Haberler, Irene Slavc, Sten Linnarsson, Johannes Gojo, Michelle Monje, Chris Jones, Mariella G Filbin.
      Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.
    DOI:  https://doi.org/10.1016/j.ccell.2024.08.006
  53. Cancer Res. 2024 Sep 06.
    MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development.
    Jane Ding, Mohit Bansal, Yuxia Cao, Bingwei Ye, Rui Mao, Anamika Gupta, Sunil Sudarshan, Han-Fei Ding.
      Pseudouridylation is a common RNA modification that is catalyzed by the family of pseudouridine synthases (PUS). Pseudouridylation can increase RNA stability and rigidity, thereby impacting RNA splicing, processing, and translation. Given that RNA metabolism is frequently altered in cancer, pseudouridylation may be a functionally important process in tumor biology. Here, we showed that the MYC family of oncoproteins transcriptionally upregulates PUS7 expression during cancer development. PUS7 was essential for the growth and survival of MYC-driven cancer cells and xenografts by promoting adaptive stress responses and amino acid biosynthesis and import. ATF4, a master regulator of stress responses and cellular metabolism, was identified as a key downstream mediator of PUS7 functional activity. Induction of ATF4 by MYC oncoproteins and cellular stress required PUS7, and ATF4 overexpression overcame the growth inhibition caused by PUS7 deficiency. Mechanistically, PUS7 induced pseudouridylation of MCTS1 mRNA, which enhanced its translation. MCTS1, a noncanonical translation initiation factor, drove stress-induced ATF4 protein expression. A PUS7 consensus pseudouridylation site in the 3' untranslated region of ATF4 mRNA was crucial for the induction of ATF4 by cellular stress. These findings unveil a MYC-activated mRNA pseudouridylation program that mitigates cellular stress induced by MYC stimulation of proliferation and biomass production, suggesting that targeting PUS7 could be therapeutic strategy selectively against MYC-driven cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1102
  54. Nat Commun. 2024 Sep 04. 15(1): 7731
    Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility.
    PARTNER Trial Group
      Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England's 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an "FFPEImpact" score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.
    DOI:  https://doi.org/10.1038/s41467-024-51577-2
  55. J Clin Invest. 2024 Sep 03. pii: e177606. [Epub ahead of print]134(17):
    Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.
    Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub.
      Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.
    Keywords:  Cancer immunotherapy; Glucose metabolism; Immunology; Metabolism; Pharmacology
    DOI:  https://doi.org/10.1172/JCI177606
  56. Nat Commun. 2024 Aug 29. 15(1): 7483
    Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
    Rongling Wang, Mario Gomez Salazar, Iris Pruñonosa Cervera, Amanda Coutts, Karen French, Marlene Magalhaes Pinto, Sabrina Gohlke, Ruben García-Martín, Matthias Blüher, Christopher J Schofield, Ioannis Kourtzelis, Roland H Stimson, Cécile Bénézech, Mark Christian, Tim J Schulz, Elias F Gudmundsson, Lori L Jennings, Vilmundur G Gudnason, Triantafyllos Chavakis, Nicholas M Morton, Valur Emilsson, Zoi Michailidou.
      Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-51718-7
  57. bioRxiv. 2024 Jul 29. pii: 2024.07.26.605362. [Epub ahead of print]
    Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.
    Rupsa Datta, Veronika Miskolci, Gina M Gallego-López, Emily Britt, Amani Gillette, Aleksandr Kralovec, Morgan A Giese, Tongcheng Qian, Jing Fan, Anna Huttenlocher, Melissa C Skala.
      Neutrophils, the most abundant leukocytes in human peripheral circulation, are crucial for the innate immune response. They are typically quiescent but rapidly activate in response to infection and inflammation, performing diverse functions such as oxidative burst, phagocytosis, and NETosis, which require significant metabolic adaptation. Deeper insights into such metabolic changes will help identify regulation of neutrophil functions in health and diseases. Due to their short lifespan and associated technical challenges, the metabolic processes of neutrophils are not completely understood. This study uses optical metabolic imaging (OMI), which entails optical redox ratio and fluorescence lifetime imaging microscopy of intrinsic metabolic coenzymes NAD(P)H and FAD to assess the metabolic state of single neutrophils. Primary human neutrophils were imaged in vitro under a variety of activation conditions and metabolic pathway inhibitors, while metabolic and functional changes were confirmed with mass spectrometry, oxidative burst, and NETosis measurements. Our findings show that neutrophils undergo rapid metabolic remodeling to a reduced redox state, followed by a shift to an oxidized redox state during activation. Additionally, single cell analysis reveals a heterogeneous metabolic response across neutrophils and donors to live pathogen infection ( Pseudomonas aeruginosa and Toxoplasma gondii ). Finally, consistent metabolic changes were validated with neutrophils in vivo using zebrafish larvae. This study demonstrates the potential of OMI as a versatile tool for studying neutrophil metabolism and underscores its use across different biological systems, offering insights into neutrophil metabolic activity and function at a single cell level.
    DOI:  https://doi.org/10.1101/2024.07.26.605362
  58. bioRxiv. 2024 Aug 06. pii: 2024.08.02.606284. [Epub ahead of print]
    Multiplex genome editing eliminates the Warburg Effect without impacting growth rate in mammalian cells.
    Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A Miguez, Sara Petersen Bjorn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G Voldborg, Nathan E Lewis.
      The Warburg effect is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production, as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production via knockout have failed in mammalian bioprocessing since lactate dehydrogenase has proven essential. However, here we eliminated the Warburg effect in Chinese hamster ovary (CHO) and HEK293 cells by simultaneously knocking out lactate dehydrogenase and regulators involved in a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. In contrast to long-standing assumptions about the role of aerobic glycolysis, Warburg-null cells maintain wildtype growth rate while producing negligible lactate. Further characterization of Warburg-null CHO cells showed a compensatory increase in oxygen consumption, a near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. These cells remained amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titers and maintaining product glycosylation. Thus, the ability to eliminate the Warburg effect is an important development for biotherapeutic production and provides a tool for investigating a near-universal metabolic phenomenon.
    DOI:  https://doi.org/10.1101/2024.08.02.606284
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