bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–08–13
thirty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
  2. Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
  3. Mitochondrial fission fueled by fasting.
  4. The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention.
  5. Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
  6. A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.
  7. The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer.
  8. Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
  9. Emerging therapies in cancer metabolism.
  10. Mitochondrial integrated stress response controls lung epithelial cell fate.
  11. TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.
  12. Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.
  13. DELE1 oligomerization promotes integrated stress response activation.
  14. NME6: ribonucleotide salvage sustains mitochondrial transcription.
  15. Mitochondrial evolution: Gene shuffling, endosymbiosis, and signaling.
  16. Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity.
  17. Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis.
  18. Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.
  19. De novo nucleotide biosynthetic pathway and cancer.
  20. Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.
  21. The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.
  22. Multiple approaches of cellular metabolism define the bacterial ancestry of mitochondria.
  23. Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
  24. Universal DNA methylation age across mammalian tissues.
  25. Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.
  26. Calculation of ATP production rates using the Seahorse XF Analyzer.
  27. Uridine: as sweet as sugar for some cells?
  28. GABA regulates electrical activity and tumor initiation in melanoma.
  29. Metabolic Oscillations and Glycolytic Phenotypes of Cancer Cells.
  30. Inflammation o'clock: interactions of circadian rhythms with inflammation-induced skeletal muscle atrophy.
  31. Lactate is a bridge linking glycolysis and autophagy through lactylation.
  1. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
      
    DOI:  https://doi.org/10.1038/s41556-023-01206-9
  2. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
    Raffaele Nicastro, Laura Brohée, Josephine Alba, Julian Nüchel, Gianluca Figlia, Stefanie Kipschull, Peter Gollwitzer, Jesus Romero-Pozuelo, Stephanie A Fernandes, Andreas Lamprakis, Stefano Vanni, Aurelio A Teleman, Claudio De Virgilio, Constantinos Demetriades.
      Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.
    DOI:  https://doi.org/10.1038/s41556-023-01198-6
  3. Sci Signal. 2023 08 08. 16(797): eadk1008
    Mitochondrial fission fueled by fasting.
    Wei Wong.
      Fasting activates mTORC2 to stimulate mitochondrial fission and support mitochondrial respiration.
    DOI:  https://doi.org/10.1126/scisignal.adk1008
  4. Cancers (Basel). 2023 Jul 25. pii: 3775. [Epub ahead of print]15(15):
    The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention.
    Sonia Domínguez-Zorita, José M Cuezva.
      Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment.
    Keywords:  ATPase inhibitory factor 1; OXPHOS; RNA binding proteins; Warburg effect; cancer; cell death; metabolic reprogramming; metastasis; mitochondrial ATP synthase; mitohormesis
    DOI:  https://doi.org/10.3390/cancers15153775
  5. Nat Metab. 2023 Aug 07.
    Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
    J N Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A Cassel, Christopher M Adams, Richard M Higashi, David A Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N Lane, Teresa W-M Fan, Ji Zhang, Ruoning Wang.
      Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.
    DOI:  https://doi.org/10.1038/s42255-023-00856-1
  6. Nat Commun. 2023 08 09. 14(1): 4816
    A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.
    Anna S Dickson, Tekle Pauzaite, Esther Arnaiz, Brian M Ortmann, James A West, Norbert Volkmar, Anthony W Martinelli, Zhaoqi Li, Niek Wit, Dennis Vitkup, Arthur Kaser, Paul J Lehner, James A Nathan.
      Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.
    DOI:  https://doi.org/10.1038/s41467-023-40541-1
  7. iScience. 2023 Aug 18. 26(8): 107360
    The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer.
    Ludovic Wesolowski, Jianfeng Ge, Leticia Castillon, Debora Sesia, Anna Dyas, Shoko Hirosue, Veronica Caraffini, Anne Y Warren, Paulo Rodrigues, Giovanni Ciriello, Saroor A Patel, Sakari Vanharanta.
      Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies.
    Keywords:  Cancer; Cellular physiology; Human genetics; Medical microbiology
    DOI:  https://doi.org/10.1016/j.isci.2023.107360
  8. Nat Commun. 2023 Aug 10. 14(1): 4726
    Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
    Ayelet M Rosenberg, Manish Saggar, Anna S Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard.
      The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
    DOI:  https://doi.org/10.1038/s41467-023-39941-0
  9. Cell Metab. 2023 Aug 08. pii: S1550-4131(23)00265-6. [Epub ahead of print]35(8): 1283-1303
    Emerging therapies in cancer metabolism.
    Yi Xiao, Tian-Jian Yu, Ying Xu, Rui Ding, Yi-Ping Wang, Yi-Zhou Jiang, Zhi-Ming Shao.
      Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.006
  10. Nature. 2023 Aug 09.
    Mitochondrial integrated stress response controls lung epithelial cell fate.
    SeungHye Han, Minho Lee, Youngjin Shin, Regina Giovanni, Ram P Chakrabarty, Mariana M Herrerias, Laura A Dada, Annette S Flozak, Paul A Reyfman, Basil Khuder, Colleen R Reczek, Lin Gao, José Lopéz-Barneo, Cara J Gottardi, G R Scott Budinger, Navdeep S Chandel.
      Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.
    DOI:  https://doi.org/10.1038/s41586-023-06423-8
  11. Cell Discov. 2023 Aug 08. 9(1): 84
    TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.
    Jing He, Mingen Lin, Xinchao Zhang, Ruonan Zhang, Tongguan Tian, Yuefan Zhou, Wenjing Dong, Yajing Yang, Xue Sun, Yue Dai, Yue Xu, Zhenru Zhang, Ming Xu, Qun-Ying Lei, Yanping Xu, Lei Lv.
      Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1-HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.
    DOI:  https://doi.org/10.1038/s41421-023-00567-7
  12. EMBO J. 2023 Aug 09. e114164
    Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.
    Andrew D Beale, Edward A Hayter, Priya Crosby, Utham K Valekunja, Rachel S Edgar, Johanna E Chesham, Elizabeth S Maywood, Fatima H Labeed, Akhilesh B Reddy, Kenneth P Wright, Kathryn S Lilley, David A Bechtold, Michael H Hastings, John S O'Neill.
      Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.
    Keywords:  body temperature; circadian rhythms; erythrocyte; haemoglobin; redox
    DOI:  https://doi.org/10.15252/embj.2023114164
  13. Nat Struct Mol Biol. 2023 Aug 07.
    DELE1 oligomerization promotes integrated stress response activation.
    Jie Yang, Kelsey R Baron, Daniel E Pride, Anette Schneemann, Xiaoyan Guo, Wenqian Chen, Albert S Song, Giovanni Aviles, Martin Kampmann, R Luke Wiseman, Gabriel C Lander.
      Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D4 symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.
    DOI:  https://doi.org/10.1038/s41594-023-01061-0
  14. EMBO J. 2023 Aug 07. e114990
    NME6: ribonucleotide salvage sustains mitochondrial transcription.
    Paulina H Wanrooij, Andrei Chabes.
      The building blocks for RNA and DNA are made in the cytosol, meaning mitochondria depend on the import and salvage of ribonucleoside triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs) for the synthesis of their own genetic material. While extensive research has focused on mitochondrial dNTP homeostasis due to its defects being associated with various mitochondrial DNA (mtDNA) depletion and deletion syndromes, the investigation of mitochondrial rNTP homeostasis has received relatively little attention. In this issue of the EMBO Journal, Grotehans et al provide compelling evidence of a major role for NME6, a mitochondrial nucleoside diphosphate kinase, in the conversion of pyrimidine ribonucleoside diphosphates into the corresponding triphosphates. These data also suggest a significant physiological role for NME6, as its absence results in the depletion of mitochondrial transcripts and destabilization of the electron transport chain (Grotehans et al, 2023).
    DOI:  https://doi.org/10.15252/embj.2023114990
  15. Sci Adv. 2023 Aug 09. 9(32): eadj4493
    Mitochondrial evolution: Gene shuffling, endosymbiosis, and signaling.
    Parth K Raval, William F Martin, Sven B Gould.
      Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic cells.
    DOI:  https://doi.org/10.1126/sciadv.adj4493
  16. Cancer Discov. 2023 Aug 07. pii: CD-23-0007. [Epub ahead of print]
    Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity.
    Andrew A Guirguis, Yaara Ofir-Rosenfeld, Kathy Knezevic, Wesley Blackaby, David Hardick, Yih-Chih Chan, Ali Motazedian, Andrea Gillespie, Dane Vassiliadis, Enid Yn Lam, Kevin Tran, Byron Andrews, Michael E Harbour, Lina Vasiliauskaite, Claire J Saunders, Georgia Tsagkogeorga, Aleksandra Azevedo, Joanna Obacz, Ewa S Pilka, Marie Carkill, Laura MacPherson, Elanor N Wainwright, Brian Liddicoat, Benjamin J Blyth, Mark R Albertella, Oliver Rausch, Mark A Dawson.
      Therapies that enhance anti-tumour immunity have altered the natural history of many cancers. Consequently, leveraging non-overlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase, METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signalling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that whilst METTL3 inhibition is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies overcome clones insensitive to the single agents. These data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinic.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0007
  17. Cancers (Basel). 2023 Aug 03. pii: 3942. [Epub ahead of print]15(15):
    Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis.
    Davide Gnocchi, Dragana Nikolic, Rosa Rita Paparella, Carlo Sabbà, Antonio Mazzocca.
      Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic-Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells "revert" to "primitive" characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells' metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a "shift" toward "atavistic" biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.
    Keywords:  cancer drug resistance; tumor adaptation; tumor biology; tumor metabolism
    DOI:  https://doi.org/10.3390/cancers15153942
  18. J Exp Clin Cancer Res. 2023 Aug 07. 42(1): 196
    Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.
    Daniele Boso, Martina Tognon, Matteo Curtarello, Sonia Minuzzo, Ilaria Piga, Valentina Brillo, Elisabetta Lazzarini, Jessica Carlet, Ludovica Marra, Chiara Trento, Andrea Rasola, Ionica Masgras, Leonardo Caporali, Fabio Del Ben, Giulia Brisotto, Matteo Turetta, Roberta Pastorelli, Laura Brunelli, Filippo Navaglia, Giovanni Esposito, Angela Grassi, Stefano Indraccolo.
       BACKGROUND: Genetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis.
    METHODS: Clonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy.
    RESULTS: Two clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation.
    CONCLUSION: A glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy.
    Keywords:  Anti-angiogenic therapy; Glucose deprivation resistance; Mitochondria; Ovarian cancer; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s13046-023-02779-x
  19. Genes Dis. 2023 Nov;10(6): 2331-2338
    De novo nucleotide biosynthetic pathway and cancer.
    Jie Chen, Siqi Yang, Yingge Li, Xu Ziwen, Pingfeng Zhang, Qibin Song, Yi Yao, Huadong Pei.
      De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the de novo nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer. It has been shown that many enzymes in this pathway are overactivated in different cancers. In this review, we summarize and update the current knowledge on the de novo nucleotide biosynthetic pathway, regulatory mechanisms, its role in tumorigenesis, and potential targeting opportunities.
    Keywords:  Biosynthetic pathway; Cancer; Metabolism; Nucleotide; de novo synthesis
    DOI:  https://doi.org/10.1016/j.gendis.2022.04.018
  20. Cold Spring Harb Perspect Med. 2023 Aug 08. pii: a041530. [Epub ahead of print]
    Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.
    Chi V Dang.
      A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.
    DOI:  https://doi.org/10.1101/cshperspect.a041530
  21. J Cell Biochem. 2023 Aug 11.
    The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.
    Di Wu, Kejia Zhang, Faheem Ahmed Khan, Qin Wu, Nuruliarizki Shinta Pandupuspitasari, Yuan Tang, Kaifeng Guan, Fei Sun, Chunjie Huang.
      Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.
    Keywords:  aerobic glycolysis; efferocytosis; lactate signaling; lactate-driven lactylation; tumor immunity
    DOI:  https://doi.org/10.1002/jcb.30458
  22. Sci Adv. 2023 Aug 09. 9(32): eadh0066
    Multiple approaches of cellular metabolism define the bacterial ancestry of mitochondria.
    Otto Geiger, Alejandro Sanchez-Flores, Jonathan Padilla-Gomez, Mauro Degli Esposti.
      We breathe at the molecular level when mitochondria in our cells consume oxygen to extract energy from nutrients. Mitochondria are characteristic cellular organelles that derive from aerobic bacteria and carry out oxidative phosphorylation and other key metabolic pathways in eukaryotic cells. The precise bacterial origin of mitochondria and, consequently, the ancestry of the aerobic metabolism of our cells remain controversial despite the vast genomic information that is now available. Here, we use multiple approaches to define the most likely living relatives of the ancestral bacteria from which mitochondria originated. These bacteria live in marine environments and exhibit the highest frequency of aerobic traits and genes for the metabolism of fundamental lipids that are present in the membranes of eukaryotes, sphingolipids, and cardiolipin.
    DOI:  https://doi.org/10.1126/sciadv.adh0066
  23. Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00981-6. [Epub ahead of print]42(8): 112970
    Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
    Tom Barsby, Eliisa Vähäkangas, Jarkko Ustinov, Hossam Montaser, Hazem Ibrahim, Väinö Lithovius, Emilia Kuuluvainen, Vikash Chandra, Jonna Saarimäki-Vire, Pekka Katajisto, Ville Hietakangas, Timo Otonkoski.
      Pancreatic islets regulate blood glucose homeostasis through the controlled release of insulin; however, current metabolic models of glucose-sensitive insulin secretion are incomplete. A comprehensive understanding of islet metabolism is integral to studies of endocrine cell development as well as diabetic islet dysfunction. Human pluripotent stem cell-derived islets (SC-islets) are a developmentally relevant model of human islet function that have great potential in providing a cure for type 1 diabetes. Using multiple 13C-labeled metabolic fuels, we demonstrate that SC-islets show numerous divergent patterns of metabolite trafficking in proposed insulin release pathways compared with primary human islets but are still reliant on mitochondrial aerobic metabolism to derive function. Furthermore, reductive tricarboxylic acid cycle activity and glycolytic metabolite cycling occur in SC-islets, suggesting that non-canonical coupling factors are also present. In aggregate, we show that many facets of SC-islet metabolism overlap with those of primary islets, albeit with a retained immature signature.
    Keywords:  Beta cells; CP: Metabolism; diabetes; insulin; islets; metabolism; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2023.112970
  24. Nat Aging. 2023 Aug 10.
    Universal DNA methylation age across mammalian tissues.
    A T Lu, Z Fei, A Haghani, T R Robeck, J A Zoller, C Z Li, R Lowe, Q Yan, J Zhang, H Vu, J Ablaeva, V A Acosta-Rodriguez, D M Adams, J Almunia, A Aloysius, R Ardehali, A Arneson, C S Baker, G Banks, K Belov, N C Bennett, P Black, D T Blumstein, E K Bors, C E Breeze, R T Brooke, J L Brown, G G Carter, A Caulton, J M Cavin, L Chakrabarti, I Chatzistamou, H Chen, K Cheng, P Chiavellini, O W Choi, S M Clarke, L N Cooper, M L Cossette, J Day, J DeYoung, S DiRocco, C Dold, E E Ehmke, C K Emmons, S Emmrich, E Erbay, C Erlacher-Reid, C G Faulkes, S H Ferguson, C J Finno, J E Flower, J M Gaillard, E Garde, L Gerber, V N Gladyshev, V Gorbunova, R G Goya, M J Grant, C B Green, E N Hales, M B Hanson, D W Hart, M Haulena, K Herrick, A N Hogan, C J Hogg, T A Hore, T Huang, J C Izpisua Belmonte, A J Jasinska, G Jones, E Jourdain, O Kashpur, H Katcher, E Katsumata, V Kaza, H Kiaris, M S Kobor, P Kordowitzki, W R Koski, M Krützen, S B Kwon, B Larison, S G Lee, M Lehmann, J F Lemaitre, A J Levine, C Li, X Li, A R Lim, D T S Lin, D M Lindemann, T J Little, N Macoretta, D Maddox, C O Matkin, J A Mattison, M McClure, J Mergl, J J Meudt, G A Montano, K Mozhui, J Munshi-South, A Naderi, M Nagy, P Narayan, P W Nathanielsz, N B Nguyen, C Niehrs, J K O'Brien, P O'Tierney Ginn, D T Odom, A G Ophir, S Osborn, E A Ostrander, K M Parsons, K C Paul, M Pellegrini, K J Peters, A B Pedersen, J L Petersen, D W Pietersen, G M Pinho, J Plassais, J R Poganik, N A Prado, P Reddy, B Rey, B R Ritz, J Robbins, M Rodriguez, J Russell, E Rydkina, L L Sailer, A B Salmon, A Sanghavi, K M Schachtschneider, D Schmitt, T Schmitt, L Schomacher, L B Schook, K E Sears, A W Seifert, A Seluanov, A B A Shafer, D Shanmuganayagam, A V Shindyapina, M Simmons, K Singh, I Sinha, J Slone, R G Snell, E Soltanmaohammadi, M L Spangler, M C Spriggs, L Staggs, N Stedman, K J Steinman, D T Stewart, V J Sugrue, B Szladovits, J S Takahashi, M Takasugi, E C Teeling, M J Thompson, B Van Bonn, S C Vernes, D Villar, H V Vinters, M C Wallingford, N Wang, R K Wayne, G S Wilkinson, C K Williams, R W Williams, X W Yang, M Yao, B G Young, B Zhang, Z Zhang, P Zhao, Y Zhao, W Zhou, J Zimmermann, J Ernst, K Raj, S Horvath.
      Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
    DOI:  https://doi.org/10.1038/s43587-023-00462-6
  25. Nat Commun. 2023 Aug 10. 14(1): 4823
    Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.
    PEACE consortium
      Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10-8 and 6.4 × 10-4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
    DOI:  https://doi.org/10.1038/s41467-023-40315-9
  26. EMBO Rep. 2023 Aug 07. e56380
    Calculation of ATP production rates using the Seahorse XF Analyzer.
    Brandon R Desousa, Kristen Ko Kim, Anthony E Jones, Andréa B Ball, Wei Y Hsieh, Pamela Swain, Danielle H Morrow, Alexandra J Brownstein, David A Ferrick, Orian S Shirihai, Andrew Neilson, David A Nathanson, George W Rogers, Brian P Dranka, Anne N Murphy, Charles Affourtit, Steven J Bensinger, Linsey Stiles, Natalia Romero, Ajit S Divakaruni.
      Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell-specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady-state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions.
    Keywords:  ATP; ECAR; Seahorse XF Analyzer; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.15252/embr.202256380
  27. Cell Res. 2023 Aug 11.
    Uridine: as sweet as sugar for some cells?
    Matthew H Ward, Zeribe C Nwosu, Costas A Lyssiotis.
      
    DOI:  https://doi.org/10.1038/s41422-023-00860-w
  28. Cancer Discov. 2023 Aug 09. pii: CD-23-0389. [Epub ahead of print]
    GABA regulates electrical activity and tumor initiation in melanoma.
    Mohita Tagore, Emiliano Hergenreder, Sarah C Perlee, Nelly M Cruz, Laura Menocal, Shruthy Suresh, Eric Chan, Maayan Baron, Stephanie Melendez, Asim Dave, Walid K Chatila, Jeremie Nsengimana, Richard P Koche, Travis J Hollmann, Trey Ideker, Lorenz Studer, Andrea Schietinger, Richard M White.
      Oncogenes can only initiate tumors in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors on keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multi-electrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte co-cultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0389
  29. Int J Mol Sci. 2023 Jul 25. pii: 11914. [Epub ahead of print]24(15):
    Metabolic Oscillations and Glycolytic Phenotypes of Cancer Cells.
    Takashi Amemiya, Kenichi Shibata, Tomohiko Yamaguchi.
      Cancer cells show several metabolic phenotypes depending on the cancer types and the microenvironments in tumor tissues. The glycolytic phenotype is one of the hallmarks of cancer cells and is considered to be one of the crucial features of malignant cancers. Here, we show glycolytic oscillations in the concentrations of metabolites in the glycolytic pathway in two types of cancer cells, HeLa cervical cancer cells and DU145 prostate cancer cells, and in two types of cellular morphologies, spheroids and monolayers. Autofluorescence from nicotinamide adenine dinucleotide (NADH) in cells was used for monitoring the glycolytic oscillations at the single-cell level. The frequencies of NADH oscillations were different among the cellular types and morphologies, indicating that more glycolytic cancer cells tended to exhibit oscillations with higher frequencies than less glycolytic cells. A mathematical model for glycolytic oscillations in cancer cells reproduced the experimental results quantitatively, confirming that the higher frequencies of oscillations were due to the higher activities of glycolytic enzymes. Thus, glycolytic oscillations are expected as a medical indicator to evaluate the malignancy of cancer cells with glycolytic phenotypes.
    Keywords:  cancer cells; feedback inhibition; glycolytic oscillations; glycolytic phenotype; malignancy; mathematical model
    DOI:  https://doi.org/10.3390/ijms241511914
  30. J Physiol. 2023 Aug 10.
    Inflammation o'clock: interactions of circadian rhythms with inflammation-induced skeletal muscle atrophy.
    Francielly Morena da Silva, Karyn A Esser, Kevin A Murach, Nicholas P Greene.
      Circadian rhythms are ∼24 h cycles evident in behaviour, physiology and metabolism. The molecular mechanism directing circadian rhythms is the circadian clock, which is composed of an interactive network of transcription-translation feedback loops. The core clock genes include Bmal1, Clock, Rev-erbα/β, Per and Cry. In addition to keeping time, the core clock regulates a daily programme of gene expression that is important for overall cell homeostasis. The circadian clock mechanism is present in all cells, including skeletal muscle fibres, and disruption of the muscle clock is associated with changes in muscle phenotype and function. Skeletal muscle atrophy is largely associated with a lower quality of life, frailty and reduced lifespan. Physiological and genetic modification of the core clock mechanism yields immune dysfunction, alters inflammatory factor expression and secretion and is associated with skeletal muscle atrophy in multiple conditions, such as ageing and cancer cachexia. Here, we summarize the possible interplay between the circadian clock modulation of immune cells, systemic inflammatory status and skeletal muscle atrophy in chronic inflammatory conditions. Although there is a clear disruption of circadian clocks in various models of atrophy, the mechanism behind such alterations remains unknown. Understanding the modulatory potential of muscle and immune circadian clocks in inflammation and skeletal muscle health is essential for the development of therapeutic strategies to protect skeletal muscle mass and function of patients with chronic inflammation.
    Keywords:  ageing; cancer cachexia; immune system; muscle clock; skeletal muscle; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1113/JP284808
  31. Autophagy. 2023 Aug 11.
    Lactate is a bridge linking glycolysis and autophagy through lactylation.
    Weixia Sun, Mengshu Jia, Yingyan Feng, Xiawei Cheng.
      Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes. However, whether lactate regulates autophagy is still unknown. We recently reported that LDHA is phosphorylated at serine 196 by ULK1 (unc-51 like kinase 1) under nutrient-deprivation conditions, promoting lactate production. Then, lactate mediates PIK3C3/VPS34 lactylation at lysine 356 and lysine 781 via acyltransferase KAT5/TIP60. PIK3C3/VPS34 lactylation enhances the association of PIK3C3/VPS34 with BECN1 (beclin 1, autophagy related), ATG14 and UVRAG, increases PIK3C3/VPS34 lipid kinase activity, promotes macroautophagy/autophagy and facilitates the endolysosomal degradation pathway. PIK3C3/VPS34 hyperlactylation induces autophagy and plays an essential role in skeletal muscle homeostasis and cancer progression. Overall, this study describes an autophagy regulation mechanism and the integration of two highly conserved life processes: glycolysis and autophagy.
    DOI:  https://doi.org/10.1080/15548627.2023.2246356
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