bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020–11–22
thirty papers selected by
Christian Frezza, University of Cambridge, MRC Cancer Unit
  1. BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors.
  2. Reweaving the Fabric of Mitochondrial Contact Sites in Astrocytes.
  3. The Metabolic Underpinnings of Ferroptosis.
  4. The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.
  5. Mitochondrial Safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering-induced Oma1 activation.
  6. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.
  7. The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia.
  8. Nucleotide-binding sites can enhance N-acylation of nearby protein lysine residues.
  9. Intracellular Transport in Cancer Metabolic Reprogramming.
  10. Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies.
  11. MFSD12 mediates the import of cysteine into melanosomes and lysosomes.
  12. Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
  13. Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress.
  14. Transient commensal clonal interactions can drive tumor metastasis.
  15. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.
  16. Hypermethylation of LATS2 Promoter and Its Prognostic Value in IDH-Mutated Low-Grade Gliomas.
  17. Mitochondrial oxidative phosphorylation in cutaneous melanoma.
  18. Mfn2 Overexpression Attenuates Cardio-Cerebrovascular Ischemia-Reperfusion Injury Through Mitochondrial Fusion and Activation of the AMPK/Sirt3 Signaling.
  19. Endoplasmic reticulum stress signals in the tumour and its microenvironment.
  20. Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells.
  21. The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis.
  22. Tension heterogeneity directs form and fate to pattern the myocardial wall.
  23. Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas.
  24. STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain.
  25. Cell type-selective secretome profiling in vivo.
  26. Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis.
  27. CD38-expressing macrophages drive age-related NAD+ decline.
  28. OPA1, a new mitochondrial target in cancer therapy.
  29. Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers.
  30. Are carcinogens electron acceptors? A novel hypothesis.
  1. Oncogene. 2020 Nov 18.
    BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors.
    Anna Han, Timothy J Purwin, Nelisa Bechtel, Connie Liao, Vivian Chua, Erin Seifert, Takami Sato, Zachary T Schug, David W Speicher, J William Harbour, Andrew E Aplin.
      Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOShigh BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlow BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.
    DOI:  https://doi.org/10.1038/s41388-020-01554-y
  2. Front Cell Dev Biol. 2020 ;8 592651
    Reweaving the Fabric of Mitochondrial Contact Sites in Astrocytes.
    Matteo Bergami, Elisa Motori.
      The endoplasmic reticulum (ER) and mitochondria are classically regarded as very dynamic organelles in cell lines. Their frequent morphological changes and repositioning underlie the transient generation of physical contact sites (so-called mitochondria-ER contacts, or MERCs) which are believed to support metabolic processes central for cellular signaling and function. The extent of regulation over these organelle dynamics has likely further achieved a higher level of complexity in polarized cells like neurons and astrocytes to match their elaborated geometries and specialized functions, thus ensuring the maintenance of MERCs at metabolically demanding locations far from the soma. Yet, live imaging of adult brain tissue has recently revealed that the true extent of mitochondrial dynamics in astrocytes is significantly lower than in cell culture settings. On one hand, this suggests that organelle dynamics in mature astroglia in vivo may be highly regulated and perhaps triggered only by defined physiological stimuli. On the other hand, this extent of control may greatly facilitate the stabilization of those MERCs required to maintain regionalized metabolic domains underlying key astrocytic functions. In this perspective, we review recent evidence suggesting that the resulting spatial distribution of mitochondria and ER in astrocytes in vivo may create the conditions for maintaining extensive MERCs within specialized territories - like perivascular endfeet - and discuss the possibility that their enrichment at these distal locations may facilitate specific forms of cellular plasticity relevant for physiology and disease.
    Keywords:  MERCs; Mfn2; astrocytes; calcium; endfoot; endoplasmic reticulum; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2020.592651
  3. Cell Metab. 2020 Oct 24. pii: S1550-4131(20)30544-1. [Epub ahead of print]
    The Metabolic Underpinnings of Ferroptosis.
    Jiashuo Zheng, Marcus Conrad.
      Acute or chronic cellular stress resulting from aberrant metabolic and biochemical processes may trigger a pervasive non-apoptotic form of cell death, generally known as ferroptosis. Ferroptosis is unique among the different cell death modalities, as it has been mostly linked to pathophysiological conditions and because several metabolic pathways, such as (seleno)thiol metabolism, fatty acid metabolism, iron handling, mevalonate pathway, and mitochondrial respiration, directly impinge on the cells' sensitivity toward lipid peroxidation and ferroptosis. Additionally, key cellular redox systems, such as selenium-dependent glutathione peroxidase 4 and the NAD(P)H/ferroptosis suppressor protein-1/ubiquinone axis, are at play that constantly surveil and neutralize oxidative damage to cellular membranes. Since this form of cell death emerges to be the root cause of a number of diseases and since it offers various pharmacologically tractable nodes for therapeutic intervention, there has been overwhelming interest in the last few years aiming for a better molecular understanding of the ferroptotic death process.
    Keywords:  FSP1; GPX4; ferroptosis; lipid peroxidation; redox metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.011
  4. Nat Metab. 2020 Nov 16.
    The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.
    Julia S Brunner, Andrea Vogel, Alexander Lercher, Michael Caldera, Ana Korosec, Marlene Pühringer, Melanie Hofmann, Alexander Hajto, Markus Kieler, Lucia Quemada Garrido, Martina Kerndl, Mario Kuttke, Ildiko Mesteri, Maria W Górna, Marta Kulik, Paulina M Dominiak, Amanda E Brandon, Emma Estevez, Casey L Egan, Florian Gruber, Martina Schweiger, Jörg Menche, Andreas Bergthaler, Thomas Weichhart, Kristaps Klavins, Mark A Febbraio, Omar Sharif, Gernot Schabbauer.
      Adipose tissue macrophages (ATMs) display tremendous heterogeneity depending on signals in their local microenvironment and contribute to the pathogenesis of obesity. The phosphoinositide 3-kinase (PI3K) signalling pathway, antagonized by the phosphatase and tensin homologue (PTEN), is important for metabolic responses to obesity. We hypothesized that fluctuations in macrophage-intrinsic PI3K activity via PTEN could alter the trajectory of metabolic disease by driving distinct ATM populations. Using mice harbouring macrophage-specific PTEN deletion or bone marrow chimeras carrying additional PTEN copies, we demonstrate that sustained PI3K activity in macrophages preserves metabolic health in obesity by preventing lipotoxicity. Myeloid PI3K signalling promotes a beneficial ATM population characterized by lipid uptake, catabolism and high expression of the scavenger macrophage receptor with collagenous structure (MARCO). Dual MARCO and myeloid PTEN deficiencies prevent the generation of lipid-buffering ATMs, reversing the beneficial actions of elevated myeloid PI3K activity in metabolic disease. Thus, macrophage-intrinsic PI3K signalling boosts metabolic health by driving ATM programmes associated with MARCO-dependent lipid uptake.
    DOI:  https://doi.org/10.1038/s42255-020-00311-5
  5. EMBO J. 2020 Nov 17. e105074
    Mitochondrial Safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering-induced Oma1 activation.
    Daisuke Murata, Tatsuya Yamada, Takeshi Tokuyama, Kenta Arai, Pedro M Quirós, Carlos López-Otín, Miho Iijima, Hiromi Sesaki.
      The connectivity of mitochondria is regulated by a balance between fusion and division. Many human diseases are associated with excessive mitochondrial connectivity due to impaired Drp1, a dynamin-related GTPase that mediates division. Here, we report a mitochondrial stress response, named mitochondrial safeguard, that adjusts the balance of fusion and division in response to increased mitochondrial connectivity. In cells lacking Drp1, mitochondria undergo hyperfusion. However, hyperfusion does not completely connect mitochondria because Opa1 and mitofusin 1, two other dynamin-related GTPases that mediate fusion, become proteolytically inactivated. Pharmacological and genetic experiments show that the activity of Oma1, a metalloprotease that cleaves Opa1, is regulated by short pulses of the membrane depolarization without affecting the overall membrane potential in Drp1-knockout cells. Re-activation of Opa1 and Mitofusin 1 in Drp1-knockout cells further connects mitochondria beyond hyperfusion, termed extreme fusion, leading to bioenergetic deficits. These findings reveal an unforeseen safeguard mechanism that prevents extreme fusion of mitochondria, thereby maintaining mitochondrial function when the balance is shifted to excessive connectivity.
    Keywords:  Drp1; Oma1; Opa1; mitochondrial fusion; mitofusin
    DOI:  https://doi.org/10.15252/embj.2020105074
  6. Nat Metab. 2020 Nov;2(11): 1284-1304
    CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.
    Claudia C S Chini, Thais R Peclat, Gina M Warner, Sonu Kashyap, Jair Machado Espindola-Netto, Guilherme C de Oliveira, Lilian S Gomez, Kelly A Hogan, Mariana G Tarragó, Amrutesh S Puranik, Guillermo Agorrody, Katie L Thompson, Kevin Dang, Starlynn Clarke, Bennett G Childs, Karina S Kanamori, Micaela A Witte, Paola Vidal, Anna L Kirkland, Marco De Cecco, Karthikeyani Chellappa, Melanie R McReynolds, Connor Jankowski, Tamara Tchkonia, James L Kirkland, John M Sedivy, Jan M van Deursen, Darren J Baker, Wim van Schooten, Joshua D Rabinowitz, Joseph A Baur, Eduardo N Chini.
      Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.
    DOI:  https://doi.org/10.1038/s42255-020-00298-z
  7. Redox Biol. 2020 Nov 05. pii: S2213-2317(20)30996-4. [Epub ahead of print]38 101791
    The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia.
    Piergiorgio La Rosa, Sara Petrillo, Riccardo Turchi, Francesco Berardinelli, Tommaso Schirinzi, Gessica Vasco, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Enrico S Bertini, Katia Aquilano, Fiorella Piemonte.
      Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.
    Keywords:  EPI-743; Ferroptosis; Friedreich ataxia; Lipid peroxides; Mitochondria; Nrf2; Redox imbalance; Sulforaphane
    DOI:  https://doi.org/10.1016/j.redox.2020.101791
  8. Sci Rep. 2020 Nov 20. 10(1): 20254
    Nucleotide-binding sites can enhance N-acylation of nearby protein lysine residues.
    Andrew M James, Anthony C Smith, Shujing Ding, Jack W Houghton, Alan J Robinson, Robin Antrobus, Ian M Fearnley, Michael P Murphy.
      Acyl-CoAs are reactive metabolites that can non-enzymatically S-acylate and N-acylate protein cysteine and lysine residues, respectively. N-acylation is irreversible and enhanced if a nearby cysteine residue undergoes an initial reversible S-acylation, as proximity leads to rapid S → N-transfer of the acyl moiety. We reasoned that protein-bound acyl-CoA could also facilitate S → N-transfer of acyl groups to proximal lysine residues. Furthermore, as CoA contains an ADP backbone this may extend beyond CoA-binding sites and include abundant Rossmann-fold motifs that bind the ADP moiety of NADH, NADPH, FADH and ATP. Here, we show that excess nucleotides decrease protein lysine N-acetylation in vitro. Furthermore, by generating modelled structures of proteins N-acetylated in mouse liver, we show that proximity to a nucleotide-binding site increases the risk of N-acetylation and identify where nucleotide binding could enhance N-acylation in vivo. Finally, using glutamate dehydrogenase as a case study, we observe increased in vitro lysine N-malonylation by malonyl-CoA near nucleotide-binding sites which overlaps with in vivo N-acetylation and N-succinylation. Furthermore, excess NADPH, GTP and ADP greatly diminish N-malonylation near their nucleotide-binding sites, but not at distant lysine residues. Thus, lysine N-acylation by acyl-CoAs is enhanced by nucleotide-binding sites and may contribute to higher stoichiometry protein N-acylation in vivo.
    DOI:  https://doi.org/10.1038/s41598-020-77261-1
  9. Front Cell Dev Biol. 2020 ;8 597608
    Intracellular Transport in Cancer Metabolic Reprogramming.
    Marte Sneeggen, Noemi Antonella Guadagno, Cinzia Progida.
      Tumor progression is a complex process consisting of several steps characterized by alterations in cellular behavior and morphology. These steps include uncontrolled cell division and proliferation, invasiveness and metastatic ability. Throughout these phases, cancer cells encounter a changing environment and a variety of metabolic stress. To meet their needs for energy while they proliferate and survive in their new environment, tumor cells need to continuously fine-tune their metabolism. The connection between intracellular transport and metabolic reprogramming during cancer progression is emerging as a central process of cellular adaptation to these changes. The trafficking of proteolytic enzymes, surface receptors, but also the regulation of downstream pathways, are all central to cancer progression. In this review, we summarize different hallmarks of cancer with a special focus on the role of intracellular trafficking in cell proliferation, epithelial to mesenchymal transition as well as invasion. We will further emphasize how intracellular trafficking contributes to the regulation of energy consumption and metabolism during these steps of cancer progression.
    Keywords:  cancer cell metabolism; cell proliferation; epithelial to mesenchymal transition; invasion; membrane trafficking
    DOI:  https://doi.org/10.3389/fcell.2020.597608
  10. Front Oncol. 2020 ;10 589508
    Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies.
    Zhefang Wang, Fanyu Liu, Ningbo Fan, Chenghui Zhou, Dai Li, Thomas Macvicar, Qiongzhu Dong, Christiane J Bruns, Yue Zhao.
      Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.
    Keywords:  cancer metabolism; combination therapy; glutaminase inhibitor; glutaminolysis; metastasis
    DOI:  https://doi.org/10.3389/fonc.2020.589508
  11. Nature. 2020 Nov 18.
    MFSD12 mediates the import of cysteine into melanosomes and lysosomes.
    Charles H Adelmann, Anna K Traunbauer, Brandon Chen, Kendall J Condon, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, David M Sabatini.
      Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions1,2. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans3,4. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation5,6. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin7-9. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
    DOI:  https://doi.org/10.1038/s41586-020-2937-x
  12. Cell. 2020 Nov 16. pii: S0092-8674(20)31400-8. [Epub ahead of print]
    Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
    Clinical Proteomic Tumor Analysis Consortium
      The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
    Keywords:  CDK 4/6 inhibitors; CPTAC; acetylation; breast cancer; genomics; immune checkpoint therapy; mass spectrometry; phosphoproteomics; proteogenomics; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2020.10.036
  13. PLoS One. 2020 ;15(11): e0242700
    Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress.
    Huaiyuan Zhang, Yu Zhao, Qi Yao, Zijing Ye, Adriana Mañas, Jialing Xiang.
      Mitochondrial fusion and fission are dynamic processes regulated by the cellular microenvironment. Under nutrient starvation conditions, mitochondrial fusion is strengthened for energy conservation. We have previously shown that newborns of Ubl4A-deficient mice were more sensitive to starvation stress with a higher rate of mortality than their wild-type littermates. Ubl4A binds with the actin-related protein Arp2/3 complex to synergize the actin branching process. Here, we showed that deficiency in Ubl4A resulted in mitochondrial fragmentation and apoptosis. A defect in the fusion process was the main cause of the mitochondrial fragmentation and resulted from a shortage of primed Arp2/3 complex pool around the mitochondria in the Ubl4A-deficient cells compared to the wild-type cells. As a result, the mitochondrial fusion process was not undertaken quickly enough to sustain starvation stress-induced cell death. Consequently, fragmented mitochondria lost their membrane integrity and ROS was accumulated to trigger caspase 9-dependent apoptosis before autophagic rescue. Furthermore, the wild-type Ubl4A, but not the Arp2/3-binding deficient mutant, could rescue the starvation-induced mitochondrial fragmentation phenotype. These results suggest that Ubl4A promotes the mitochondrial fusion process via Arp2/3 complex during the initial response to nutrient deprivation for cell survival.
    DOI:  https://doi.org/10.1371/journal.pone.0242700
  14. Nat Commun. 2020 11 16. 11(1): 5799
    Transient commensal clonal interactions can drive tumor metastasis.
    Suha Naffar-Abu Amara, Hendrik J Kuiken, Laura M Selfors, Timothy Butler, Marco L Leung, Cheuk T Leung, Elaine P Kuhn, Teodora Kolarova, Carina Hage, Kripa Ganesh, Richard Panayiotou, Rosemary Foster, Bo R Rueda, Athena Aktipis, Paul Spellman, Tan A Ince, Joanne Xiu, Matthew Oberley, Zoran Gatalica, Nicholas Navin, Gordon B Mills, Rodrick T Bronson, Joan S Brugge.
      The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit-and-run" commensal interactions.
    DOI:  https://doi.org/10.1038/s41467-020-19584-1
  15. Nat Metab. 2020 Nov;2(11): 1265-1283
    Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.
    Anthony J Covarrubias, Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G Kasler, Mark S Schmidt, Indra Heckenbach, Ryan Kwok, Christopher D Wiley, Hoi-Shan Wong, Eddy Gibbs, Shankar S Iyer, Nathan Basisty, Qiuxia Wu, Ik-Jung Kim, Elena Silva, Kaitlyn Vitangcol, Kyong-Oh Shin, Yong-Moon Lee, Rebeccah Riley, Issam Ben-Sahra, Melanie Ott, Birgit Schilling, Morten Scheibye-Knudsen, Katsuhiko Ishihara, Stephen R Quake, John Newman, Charles Brenner, Judith Campisi, Eric Verdin.
      Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.
    DOI:  https://doi.org/10.1038/s42255-020-00305-3
  16. Front Cell Dev Biol. 2020 ;8 586581
    Hypermethylation of LATS2 Promoter and Its Prognostic Value in IDH-Mutated Low-Grade Gliomas.
    Yuan Gu, Yu Wang, Yebin Wang, Jiaqian Luo, Xin Wang, Mingyue Ma, Wei Hua, Ying Liu, Fa-Xing Yu.
      Mutations in the enzyme isocitrate dehydrogenase 1/2 (IDH1/2) are the most common somatic mutations in low-grade glioma (LGG). The Hippo signaling pathway is known to play a key role in organ size control, and its dysregulation is involved in the development of diverse cancers. Large tumor suppressor 1/2 (LATS1/2) are core Hippo pathway components that phosphorylate and inactivate Yes-associated protein (YAP), a transcriptional co-activator that regulates expression of genes involved in tumorigenesis. A recent report from The Cancer Genome Atlas (TCGA) has highlighted a frequent hypermethylation of LATS2 in IDH-mutant LGG. However, it is unclear if LATS2 hypermethylation is associated with YAP activation and prognosis of LGG patients. Here, we performed a network analysis of the status of the Hippo pathway in IDH-mutant LGG samples and determined its association with cancer prognosis. Combining TCGA data with our biochemical assays, we found hypermethylation of LATS2 promoter in IDH-mutant LGG. LATS2 hypermethylation, however, did not translate into YAP activation but highly correlated with IDH mutation. LATS2 hypermethylation may thus serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.
    Keywords:  Hippo pathway; IDH1/2; Lats2; YAP; isocitrate dehydrogenase; low-grade glioma
    DOI:  https://doi.org/10.3389/fcell.2020.586581
  17. Br J Cancer. 2020 Nov 18.
    Mitochondrial oxidative phosphorylation in cutaneous melanoma.
    Prakrit R Kumar, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth, Marc D Moncrieff.
      The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.
    DOI:  https://doi.org/10.1038/s41416-020-01159-y
  18. Front Cell Dev Biol. 2020 ;8 598078
    Mfn2 Overexpression Attenuates Cardio-Cerebrovascular Ischemia-Reperfusion Injury Through Mitochondrial Fusion and Activation of the AMPK/Sirt3 Signaling.
    Min Liu, Xiaoyang Li, Dezhi Huang.
      Mitochondria are potential targets for the treatment of cardio-cerebrovascular ischemia-reperfusion (I/R) injury. However, the role of the mitofusin 2 (Mfn2) protein in regulating mitochondrial fusion and cell survival has not been investigated. In the present study, an adenovirus-mediated Mfn2 overexpression assay was performed to understand the effects of Mfn2 on mitochondrial function and cell damage during cardio-cerebrovascular I/R injury. After exposure to I/R injury in vitro, the transcription and expression of Mfn2 were significantly downregulated, which correlated with decreased cell viability and increased apoptosis. By contrast, overexpression of Mfn2 significantly repressed I/R-mediated cell death through modulation of glucose metabolism and oxidative stress. Furthermore, Mfn2 overexpression improved mitochondrial fusion in cells, an effect that was followed by increased mitochondrial membrane potential, improved mitophagy, and inhibition of mitochondria-mediated apoptosis. Our data also demonstrated that Mfn2 overexpression was associated with activation of the AMPK/Sirt3 signaling pathway. Inhibition of the AMPK/Sirt3 pathway abolished the protective effects of Mfn2 on I/R-induced cell injury arising from mitochondrial damage. Our results indicate that Mfn2 protects against cardio-cerebrovascular I/R injury by augmenting mitochondrial fusion and activating the AMPK/Sirt3 signaling pathway.
    Keywords:  AMPK/Sirt3 signaling pathway; apoptosis; cardio-cerebrovascular ischemia–reperfusion (I/R) injury; mitochondrial fusion; mitofusin 2 (Mfn2)
    DOI:  https://doi.org/10.3389/fcell.2020.598078
  19. Nat Rev Cancer. 2020 Nov 19.
    Endoplasmic reticulum stress signals in the tumour and its microenvironment.
    Xi Chen, Juan R Cubillos-Ruiz.
      Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.
    DOI:  https://doi.org/10.1038/s41568-020-00312-2
  20. Dev Cell. 2020 Nov 10. pii: S1534-5807(20)30835-2. [Epub ahead of print]
    Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells.
    Jonathon M Muncie, Nadia M E Ayad, Johnathon N Lakins, Xufeng Xue, Jianping Fu, Valerie M Weaver.
      Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level forces. Whether cell tension regulates development by modifying morphogen signaling is less clear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization, which motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that recapitulate the biophysical properties of the early embryo and mediate the self-organization of "gastrulation-like" nodes in cultured hESCs. Tissue geometries that generated local nodes of high cell-adhesion tension directed the spatial patterning of the BMP4-dependent "gastrulation-like" phenotype by enhancing phosphorylation and junctional release of β-catenin to promote Wnt signaling and mesoderm specification. Furthermore, direct force application via mechanical stretching promoted BMP-dependent mesoderm specification, confirming that tissue-level forces can directly regulate cell fate specification in early human development.
    Keywords:  cytoskeletal tension; gastrulation; human embryonic stem cells; mesoderm; polyacrylamide hydrogels; self-organization; tissue patterning; traction force microscopy
    DOI:  https://doi.org/10.1016/j.devcel.2020.10.015
  21. Cancer Discov. 2020 Nov 17. pii: CD-19-1500. [Epub ahead of print]
    The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis.
    Xin Hong, Whijae Roh, Ryan J Sullivan, Keith H K Wong, Ben S Wittner, Hongshan Guo, Taronish D Dubash, Moshe Sade-Feldman, Benjamin Wesley, Elad Horwitz, Genevieve M Boland, Dieuwke L Marvin, Todd Bonesteel, Chenyue Lu, François Aguet, Risa Burr, Samuel S Freeman, Laxmi Parida, Katherine Calhoun, Michelle K Jewett, Linda T Nieman, Nir Hacohen, Anders M Näär, David T Ting, Mehmet Toner, Shannon L Stott, Gad Getz, Shyamala Maheswaran, Daniel A Haber.
      Circulating tumor cells (CTCs) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastasis. We show that single CTCs from melanoma patients coordinately upregulate lipogenesis and iron homeostasis pathways. These are correlated with both intrinsic and acquired resistance to BRAF inhibitors across clonal cultures of BRAF-mutant CTCs. The lipogenesis regulator SREBF2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species (ROS) and lipid peroxidation, thereby conferring resistance to inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic anti-oxidants Ferrostatin-1 and Vitamin E. In a prospective melanoma cohort, presence of CTCs with high lipogenic and iron metabolic RNA signatures is correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBF2-driven iron homeostatic pathways contribute to cancer progression, drug resistance and metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1500
  22. Nature. 2020 Nov 18.
    Tension heterogeneity directs form and fate to pattern the myocardial wall.
    Rashmi Priya, Srinivas Allanki, Alessandra Gentile, Shivani Mansingh, Veronica Uribe, Hans-Martin Maischein, Didier Y R Stainier.
      How diverse cell fates and complex forms emerge and feed back to each other to sculpt functional organs remains unclear. In the developing heart, the myocardium transitions from a simple epithelium to an intricate tissue that consists of distinct layers: the outer compact and inner trabecular layers. Defects in this process, which is known as cardiac trabeculation, cause cardiomyopathies and embryonic lethality, yet how tissue symmetry is broken to specify trabecular cardiomyocytes is unknown. Here we show that local tension heterogeneity drives organ-scale patterning and cell-fate decisions during cardiac trabeculation in zebrafish. Proliferation-induced cellular crowding at the tissue scale triggers tension heterogeneity among cardiomyocytes of the compact layer and drives those with higher contractility to delaminate and seed the trabecular layer. Experimentally, increasing crowding within the compact layer cardiomyocytes augments delamination, whereas decreasing it abrogates delamination. Using genetic mosaics in trabeculation-deficient zebrafish models-that is, in the absence of critical upstream signals such as Nrg-Erbb2 or blood flow-we find that inducing actomyosin contractility rescues cardiomyocyte delamination and is sufficient to drive cardiomyocyte fate specification, as assessed by Notch reporter expression in compact layer cardiomyocytes. Furthermore, Notch signalling perturbs the actomyosin machinery in cardiomyocytes to restrict excessive delamination, thereby preserving the architecture of the myocardial wall. Thus, tissue-scale forces converge on local cellular mechanics to generate complex forms and modulate cell-fate choices, and these multiscale regulatory interactions ensure robust self-organized organ patterning.
    DOI:  https://doi.org/10.1038/s41586-020-2946-9
  23. J Endocr Soc. 2020 Dec 01. 4(12): bvaa071
    Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas.
    Sunita M C De Sousa, John Toubia, Tristan S E Hardy, Jinghua Feng, Paul Wang, Andreas W Schreiber, Joel Geoghegan, Rachel Hall, Lesley Rawlings, Michael Buckland, Catherine Luxford, Talia Novos, Roderick J Clifton-Bligh, Nicola K Poplawski, Hamish S Scott, David J Torpy.
       Context: Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2-collectively, "SDHx") have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline SDHx mutation.
    Methods: We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA.
    Results: Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect.
    Conclusions: This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.
    Keywords:  SDHC; intronic mutation; paraganglioma; succinate dehydrogenase; whole-exome sequencing
    DOI:  https://doi.org/10.1210/jendso/bvaa071
  24. J Cell Biol. 2020 Dec 07. pii: e202009128. [Epub ahead of print]219(12):
    STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain.
    Tara D Fischer, Chunxin Wang, Benjamin S Padman, Michael Lazarou, Richard J Youle.
      Following the detection of cytosolic double-stranded DNA from viral or bacterial infection in mammalian cells, cyclic dinucleotide activation of STING induces interferon β expression to initiate innate immune defenses. STING activation also induces LC3B lipidation, a classical but equivocal marker of autophagy, that promotes a cell-autonomous antiviral response that arose before evolution of the interferon pathway. We report that STING activation induces LC3B lipidation onto single-membrane perinuclear vesicles mediated by ATG16L1 via its WD40 domain, bypassing the requirement of canonical upstream autophagy machinery. This process is blocked by bafilomycin A1 that binds and inhibits the vacuolar ATPase (V-ATPase) and by SopF, a bacterial effector that catalytically modifies the V-ATPase to inhibit LC3B lipidation via ATG16L1. These results indicate that activation of the cGAS-STING pathway induces V-ATPase-dependent LC3B lipidation that may mediate cell-autonomous host defense, an unanticipated mechanism that is distinct from LC3B lipidation onto double-membrane autophagosomes.
    DOI:  https://doi.org/10.1083/jcb.202009128
  25. Nat Chem Biol. 2020 Nov 16.
    Cell type-selective secretome profiling in vivo.
    Wei Wei, Nicholas M Riley, Andrew C Yang, Joon T Kim, Stephanie M Terrell, Veronica L Li, Marta Garcia-Contreras, Carolyn R Bertozzi, Jonathan Z Long.
      Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.
    DOI:  https://doi.org/10.1038/s41589-020-00698-y
  26. J Biol Chem. 2020 Nov 18. pii: jbc.RA120.014888. [Epub ahead of print]
    Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis.
    Jonathan S Rink, Adam Lin, Kaylin M McMahon, Andrea E Calvert, Shuo Yang, Tim Taxter, Jonathan Moreira, Amy Chadburn, Amir Behdad, Reem Karmali, C Shad Thaxton, Leo I Gordon.
      Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells towards increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake-addicted lymphoma cells abolishes GPX4 resulting in cancer cell death by a mechanism consistent with ferroptosis.
    Keywords:  Ferroptosis; cholesterol; cholesterol metabolism; glutathione peroxidase; high-density lipoprotein (HDL); lipid peroxidation; lymphoma; nanotechnology
    DOI:  https://doi.org/10.1074/jbc.RA120.014888
  27. Nat Metab. 2020 Nov;2(11): 1186-1187
    CD38-expressing macrophages drive age-related NAD+ decline.
    Shuai Wu, Rugang Zhang.
      
    DOI:  https://doi.org/10.1038/s42255-020-00292-5
  28. Aging (Albany NY). 2020 Nov 13. 12(21): 20931-20933
    OPA1, a new mitochondrial target in cancer therapy.
    Stephanie Herkenne, Luca Scorrano.
      
    Keywords:  OPA1; angiogenesis; cancer; mitochondria
    DOI:  https://doi.org/10.18632/aging.104207
  29. Nat Commun. 2020 Nov 20. 11(1): 5911
    Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers.
    Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi.
      Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
    DOI:  https://doi.org/10.1038/s41467-020-19593-0
  30. Med Hypotheses. 2020 Sep 02. pii: S0306-9877(20)32293-3. [Epub ahead of print]144 110235
    Are carcinogens electron acceptors? A novel hypothesis.
    U S Vishal Rao, Gururaj Arakeri, Anand Subash, M Venkatesh, Peter A Brennan.
      Carcinogens play a key role in cancer initiation. Conventional theories support the concept of genetic changes inducing tumorigenesis through proteomics and metabolomics which lead to cancer development. Current research provides evidence that metabolic genes may be altered long before mutation of tumour suppressor genes, strongly suggesting that metabolic changes may be preceding the changes seen at a genetic level. Since cancer has long been known to occur through gene regulation, an impaired cellular respiration without utilizing mitochondrial function has been an area of active interest. We hypothesize the activity of carcinogens as electron acceptors to disrupt the normal glycolysis cycle happening in a cell by acting as positive ligands. The continuous restoration of NAD+ to cytosol by oxidation of NADH with carcinogen as electron acceptor creates a metabolic pathway to assist in the carcinogenic process. This metabolic pathway continues through an adaptive process, supplemented by pyruvate converting to lactate providing a constant pool of NAD+ to continue the glycolytic pathway. We also hypothesize that carcinogenesis occurs as a precursor to metabolic stress which may promote altered genetic and protein expression causing aberrant epigenetic and cell signaling pathways.
    Keywords:  Carcinogeneses; Electron acceptors; Epigenetic pathway; Hypotheses; Metabolic stress
    DOI:  https://doi.org/10.1016/j.mehy.2020.110235
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