Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation — control of cell fate, survival and proliferation — are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.
Metabolism is linked to key processes that are required for tumour initiation: cell fate control, survival, biomass accumulation and proliferation.
Through their role as co-substrates for chromatin-modifying enzymes, metabolites have the potential to influence cell fate programmes that control tumour initiation.
Hereditary cancer syndromes highlight how mutations in metabolic enzymes can predispose to cancer through the accumulation of the oncometabolites succinate, fumarate and 2-hydroxyglutarate.
The intrinsic metabolic configurations of tissues or cells might facilitate or antagonize oncogenic transformation.
Environmental factors, including diet, inflammation, hypoxia and nutrient availability, interact to control many processes related to tumour initiation and progression.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
Frede, J., Adams, D. J. & Jones, P. H. Mutation, clonal fitness and field change in epithelial carcinogenesis. J. Pathol. 234, 296–301 (2014).
Haigis, K. M., Cichowski, K. & Elledge, S. J. Tissue-specificity in cancer: the rule, not the exception. Science 363, 1150–1151 (2019).
Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Vander Heiden, M. G. & DeBerardinis, R. J. Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).
Martínez-Reyes, I. & Chandel, N. S. Cancer metabolism: looking forward. Nat. Rev. Cancer 21, 669–680 (2021).
Ishizawa, K. et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 7, 279–282 (2010).
Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).
Blanpain, C. Tracing the cellular origin of cancer. Nat. Cell Biol. 15, 126–134 (2013).
Brown, S. et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548, 334–337 (2017).
Dow, L. E. et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 161, 1539–1552 (2015).
Ying, Z., Sandoval, M. & Beronja, S. Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth. Nat. Cell Biol. 20, 1256–1266 (2018).
Warrell, R. P. et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324, 1385–1393 (1991).
Chakrabarty, R. P. & Chandel, N. S. Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell 28, 394–408 (2021).
Intlekofer, A. M. & Finley, L. W. S. Metabolic signatures of cancer cells and stem cells. Nat. Metab. 1, 177–188 (2019).
Laugesen, A. & Helin, K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell 14, 735–751 (2014).
Reid, M. A., Dai, Z. & Locasale, J. W. The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat. Cell Biol. 19, 1298–1306 (2017).
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).
Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).
Fan, J., Krautkramer, K. A., Feldman, J. L. & Denu, J. M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10, 95–108 (2015).
Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Schvartzman, J. M., Thompson, C. B. & Finley, L. W. S. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 217, 2247–2259 (2018).
Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2014).
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).
Su, X., Wellen, K. E. & Rabinowitz, J. D. Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30, 52–60 (2016).
Martínez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).
Baksh, S. C. & Finley, L. W. S. Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases. Trends Cell Biol. 31, 24–36 (2021).
Pirozzi, C. J. & Yan, H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol. 18, 645–661 (2021).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Chowdhury, R. et al. The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Morris, J. P. IV et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature 573, 595–599 (2019).
Tran, T. Q. et al. α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nat. Cancer 1, 345–358 (2020).
Gupta, P. B., Pastushenko, I., Skibinski, A., Blanpain, C. & Kuperwasser, C. Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell 24, 65–78 (2019).
Khacho, M. et al. Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19, 232–247 (2016).
Cheung, E. C. & Vousden, K. H. The role of ROS in tumour development and progression. Nat. Rev. Cancer 22, 280–297 (2022).
Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).
Strasser, A. & Vaux, D. L. Cell death in the origin and treatment of cancer. Mol. Cell 78, 1045–1054 (2020).
Harris, I. S. & DeNicola, G. M. The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol. 30, 440–451 (2020).
Stockwell, B. R. & Jiang, X. The chemistry and biology of ferroptosis. Cell Chem. Biol. 27, 365–375 (2020).
Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 22, 381–396 (2022).
Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Green, D. R., Galluzzi, L. & Kroemer, G. Metabolic control of cell death. Science 345, 1250256 (2014).
Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).
Andersen, J. L. & Kornbluth, S. The tangled circuitry of metabolism and apoptosis. Mol. Cell 49, 399–410 (2013).
Jiang, X., Overholtzer, M. & Thompson, C. B. Autophagy in cellular metabolism and cancer. J. Clin. Invest. 125, 47–54 (2015).
Carneiro, B. A. & El-Deiry, W. S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 17, 395–417 (2020).
Santana-Codina, N., Mancias, J. D. & Kimmelman, A. C. The role of autophagy in cancer. Annu. Rev. Cancer Biol. 1, 19–39 (2017).
Kim, S. M. et al. PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells. Cancer Discov. 8, 866–883 (2018).
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
Garcia-Bermudez, J. et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118–122 (2019).
Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).
Au, E., Wong, G. & Chapman, J. R. Cancer in kidney transplant recipients. Nat. Rev. Nephrol. 14, 508–520 (2018).
Jhunjhunwala, S., Hammer, C. & Delamarre, L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat. Rev. Cancer 21, 298–312 (2021).
Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).
Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).
Agudo, J. et al. Quiescent tissue stem cells evade immune surveillance. Immunity 48, 271–285.e5 (2018).
Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016). This study shows that the metabolic networks that support proliferation differ when cancer cells are grown in vitro and in vivo.
Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife 6, e27713 (2017).
Cantor, J. R. et al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 169, 258–272.e17 (2017).
Vande Voorde, J. et al. Improving the metabolic fidelity of cancer models with a physiological cell culture medium. Sci. Adv. 5, eaau7314 (2019).
Rossiter, N. J. et al. CRISPR screens in physiologic medium reveal conditionally essential genes in human cells. Cell Metab. 33, 1248–1263.e9 (2021).
Shi, X. et al. Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS. Nat. Commun. 13, 2483 (2022).
Zhu, X. G. et al. Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells. Cell Metab. 33, 211–221.e6 (2021).
Biancur, D. E. et al. Functional genomics identifies metabolic vulnerabilities in pancreatic cancer. Cell Metab. 33, 199–210.e8 (2021).
Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).
Venneti, S. et al. Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci. Transl Med. 7, 274ra17 (2015).
Nelson, D. L. & Cox, M. M. Lehninger Principles of Biochemistry 8th edn (W.H. Freeman, 2021).
Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).
Pavlova, N. N., Zhu, J. & Thompson, C. B. The hallmarks of cancer metabolism: still emerging. Cell Metab. 34, 355–377 (2022).
Hosios, A. M. & Vander Heiden, M. G. The redox requirements of proliferating mammalian cells. J. Biol. Chem. 293, 7490–7498 (2018).
Mayers, J. R. & Vander Heiden, M. G. Nature and nurture: what determines tumor metabolic phenotypes? Cancer Res. 77, 3131–3134 (2017).
Kim, J. & DeBerardinis, R. J. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434–446 (2019).
Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016). This study induced pancreatic and lung cancer in mice via Trp53 deletion and Kras activation and found that, despite similar oncogenic lesions, only lung tumours required metabolism of branched-chain amino acids.
Rinaldi, G. et al. In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis, but not of primary breast tumors, to mTORC1 inhibition. Mol. Cell 81, 386–397.e7 (2021).
Basnet, H. et al. Flura-seq identifies organ-specific metabolic adaptations during early metastatic colonization. eLife 8, e43627 (2019).
Yuneva, M. O. et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157–170 (2012). Overexpression of either of the oncogenes MYC or MET to induce tumour formation results in differential activation of central metabolic networks depending on both initiating mutation and tissue of origin.
Jun, S. et al. The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage. Cell Metab. 33, 1777–1792 (2021).
Mahendralingam, M. J. et al. Mammary epithelial cells have lineage-rooted metabolic identities. Nat. Metab. 3, 665–681 (2021). This study shows that the metabolic profile of different mamary cell populations is conserved in the resulting breast cancer subtypes.
Chen, P.-H. et al. Metabolic diversity in human non-small cell lung cancer cells. Mol. Cell 76, 838–851.e5 (2019). This comprehensive study reports a detailed metabolic profiling of over 80 NSCLC cell lines.
Sullivan, M. R. et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 29, 1410–1421.e4 (2019).
DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).
Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).
Sciacovelli, M., Schmidt, C., Maher, E. R. & Frezza, C. Metabolic drivers in hereditary cancer syndromes. Annu. Rev. Cancer Biol. 4, 77–97 (2020).
Kaelin, W. G. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).
Clark, G. R. et al. Germline FH mutations presenting with pheochromocytoma. J. Clin. Endocrinol. Metab. 99, E2046–E2050 (2014).
Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).
Vanharanta, S. et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am. J. Hum. Genet. 74, 153–159 (2004).
Janeway, K. A. et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Natl Acad. Sci. USA 108, 314–318 (2010).
Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).
Gimenez-Roqueplo, A.-P. et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am. J. Hum. Genet. 69, 1186–1197 (2001).
Armstrong, N. et al. SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas. Cell Rep. 38, 110453 (2022).
Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016). This is the first report of a causative link between fumarate accumulation and the epithelial-to-mesenchymal transition, a process implicated in cancer initiation.
Sulkowski, P. L. et al. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat. Genet. 50, 1086–1092 (2018).
Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl Med. 9, eaal2463 (2017).
Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S. & Schumacker, P. T. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol. Cell. Biol. 28, 718–731 (2008).
Alderson, N. L. et al. S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch. Biochem. Biophys. 450, 1–8 (2006).
Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011).
Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).
Sciacovelli, M. & Frezza, C. Oncometabolites: unconventional triggers of oncogenic signalling cascades. Free Radic. Biol. Med. 100, 175–181 (2016).
Platero-Luengo, A. et al. An O2-sensitive glomus cell-stem cell synapse induces carotid body growth in chronic hypoxia. Cell 156, 291–303 (2014).
Bardella, C., Pollard, P. J. & Tomlinson, I. SDH mutations in cancer. Biochim. Biophys. Acta Bioenerg. 1807, 1432–1443 (2011).
Medeiros, B. C. et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31, 272–281 (2016).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009).
Lu, C. et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27, 1986–1998 (2013).
Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732–741 (2017).
Fukumoto, K., Nguyen, T. B., Chiba, S. & Sakata-Yanagimoto, M. Review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T-cell lymphoma. Cancer Sci. 109, 490–496 (2018).
Butzmann, A. et al. A comprehensive analysis of RHOA mutation positive and negative angioimmunoblastic T-cell lymphomas by targeted deep sequencing, expression profiling and single cell digital image analysis. Int. J. Mol. Med. 46, 1466–1476 (2020).
Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).
Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).
Lin, A.-P. et al. D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat. Commun. 6, 7768 (2015).
Gorelick, A. N. et al. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat. Metab. 3, 558–570 (2021).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Labuschagne, C. F., Zani, F. & Vousden, K. H. Control of metabolism by p53 – cancer and beyond. Biochim. Biophys. Acta Rev. Cancer 1870, 32–42 (2018).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Morris, J. P., Wang, S. C. & Hebrok, M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 10, 683–695 (2010).
Carrer, A. et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416–435 (2019). Kras-mutant acinar cells exhibit high levels of acetyl-CoA that fuel cancer cell histone acetylation and acinar-to-ductal metaplasia; accordingly, deletion of Acly, the gene encoding an acetyl-CoA-producing enzyme, reduces tumour incidence and prolongs survival in mouse models of pancreatic cancer.
Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476–481 (2017).
Bonnay, F. et al. Oxidative metabolism drives immortalization of neural stem cells during tumorigenesis. Cell 182, 1490–1507.e19 (2020).
Schell, J. C. et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell 56, 400–413 (2014).
Bensard, C. L. et al. Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell Metab. 31, 284–300.e7 (2020). This study demonstrates that loss of the mitochondrial pyruvate carrier in the intestine induces a metabolic programme that predisposes to cancer initiation.
Perez-Ramirez, C. A. & Christofk, H. R. Challenges in studying stem cell metabolism. Cell Stem Cell 28, 409–423 (2021).
Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).
Janiszewska, M. et al. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. 26, 1926–1944 (2012).
Kuntz, E. M. et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat. Med. 23, 1234–1240 (2017).
Vazquez, F. et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 (2013).
Rao, S. et al. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell Res. 29, 579–591 (2019).
Raffel, S. et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384–388 (2017).
Schaaf, M. B., Garg, A. D. & Agostinis, P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis. 9, 115 (2018).
Schito, L. & Semenza, G. L. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2, 758–770 (2016).
Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).
Ito, K. & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256 (2014).
Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019).
Intlekofer, A. M. et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015).
Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015).
Shim, E.-H. et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).
Wahl, D. R. & Venneti, S. 2-Hydoxyglutarate: D/Riving Pathology in gLiomaS. Brain Pathol. 25, 760–768 (2015).
Vladoiu, M. C. et al. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature 572, 67–73 (2019).
Michealraj, K. A. et al. Metabolic regulation of the epigenome drives lethal infantile ependymoma. Cell 181, 1329–1345.e4 (2020).
Mack, S. C. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014).
Panwalkar, P. et al. Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas. Sci. Transl Med. 13, eabc0497 (2021).
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016). This study shows that poorly vascularized areas in the tumour core exhibit low glutamine levels that are associated with cancer cell histone hypermethylation, dedifferentiation and drug resistance.
Ishak Gabra, M. B. et al. Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth. Nat. Commun. 11, 3326 (2020).
Baksh, S. C. et al. Extracellular serine controls epidermal stem cell fate and tumour initiation. Nat. Cell Biol. 22, 779–790 (2020). This study links local nutrient abundance to stem cell differentiation and tumour initiation, showing that serine restriction induces tumour-suppressive differentiation in epidermal stem cells and squamous cell carcinoma by forcing cells to engage in de novo serine synthesis, which produces α-ketoglutarate.
Loenarz, C. & Schofield, C. J. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem. Sci. 36, 7–18 (2011).
Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095.e20 (2017).
Rappez, L. et al. SpaceM reveals metabolic states of single cells. Nat. Methods 18, 799–805 (2021).
Jang, C. et al. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30, 594–606.e3 (2019).
Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A. & Wargo, J. A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33, 570–580 (2018).
Janney, A., Powrie, F. & Mann, E. H. Host-microbiota maladaptation in colorectal cancer. Nature 585, 509–517 (2020).
Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Chang, P. V., Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).
Bell, H. N. et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell 40, 185–200.e6 (2022).
Kadosh, E. et al. The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. Nature 586, 133–138 (2020).
Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).
Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).
Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).
Gaber, T., Strehl, C. & Buttgereit, F. Metabolic regulation of inflammation. Nat. Rev. Rheumatol. 13, 267–279 (2017).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Alonso-Curbelo, D. et al. A gene–environment-induced epigenetic program initiates tumorigenesis. Nature 590, 642–648 (2021).
Morris, J. P. T., Cano, D. A., Sekine, S., Wang, S. C. & Hebrok, M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).
Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
Li, F. et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat. Cell Biol. 22, 728–739 (2020).
Arnold, M. et al. Obesity and cancer: an update of the global impact. Cancer Epidemiol. 41, 8–15 (2016).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Tajan, M. & Vousden, K. H. Dietary approaches to cancer therapy. Cancer Cell 37, 767–785 (2020).
Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508–512 (2014).
Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935.e5 (2021).
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
Chung, K. M. et al. Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma. Cell 181, 832–847.e18 (2020).
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016). This study shows that dietary fat ingestion can increase self-renewal capacity in intestinal progenitors and contribute to the development of spontaneous intestinal tumours in vivo.
Ringel, A. E. et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 183, 1848–1866.e26 (2020).
Mana, M. D. et al. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell Rep. 35, 109212 (2021).
Cheng, C.-W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131.e15 (2019).
Dmitrieva-Posocco, O. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022).
Geidl-Flueck, B. et al. Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: a randomized controlled trial. J. Hepatol. 75, 46–54 (2021).
Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).
Bian, Y. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277–282 (2020).
Lim, A. R., Rathmell, W. K. & Rathmell, J. C. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife 9, e55185 (2020).
Courtney, K. D. et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28, 793–800.e2 (2018).
Sack, L. M. et al. Profound tissue specificity in proliferation control underlies cancer drivers and aneuploidy patterns. Cell 173, 499–514.e23 (2018).
Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304.e6 (2018).
Carmona-Fontaine, C. et al. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl Acad. Sci. USA 114, 2934–2939 (2017).
Tasdogan, A. et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115–120 (2019).
Lee, J. S. et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell 174, 1559–1570.e22 (2018).
Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282–288 (2021).
Chang, C.-H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Ho, P.-C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).
Leone, R. D. & Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20, 516–531 (2020).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293.e7 (2017).
Luengo, A., Gui, D. Y. & Vander Heiden, M. G. Targeting metabolism for cancer therapy. Cell Chem. Biol. 24, 1161–1180 (2017).
Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).
Maddocks, O. D. K. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2012).
Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401 (2019).
The authors thank S. Baksh (Sloan Kettering Institute, USA) for critical reading of the manuscript and members of the Finley laboratory for helpful discussion. L.W.S.F. is a Searle Scholar. The authors acknowledge the support of a Human Frontier Science Program Fellowship LT000200/2021-L (to J.S.B.), grants to L.W.S.F. from the Pershing Square Sohn Prize for Cancer Research and the NIH/NCI (R37CA252305), and the Memorial Sloan Kettering Cancer Center Support Grant P30CA008748.
The authors declare no competing interests.
Peer review information
Nature Reviews Endocrinology thanks Christian Frezza and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- α-ketoglutarate-dependent dioxygenases
A family of iron-containing enzymes that use molecular oxygen and α-ketoglutarate to oxidize a substrate, producing succinate and carbon dioxide as by-products.
Influx of intermediates into the tricarboxylic acid cycle.
The process by which cellular components are delivered to the lysosome for digestion.
Efflux of intermediates from the tricarboxylic acid cycle to other metabolic pathways.
- Conditional essentiality
While essential genes are broadly considered to be required for cell viability under a wide array of conditions, genes exhibiting conditional essentiality are required for cell viability under specific circumstances, such as loss of another gene, activation of a signalling pathway or restriction of extracellular nutrients.
- Epithelial–mesenchymal transition
A process in which epithelial cells change fate towards mesenchymal lineages, thereby gaining migratory capacity, invasiveness and often stem-like features.
- Homeostatic stem cells
Undifferentiated progenitor cells that maintain tissue integrity by balancing self-renewal and differentiation into mature cells.
- Isotope-tracing studies
Experiments in which heavy-labelled atoms are followed through metabolic networks, often by incubating cells with labelled forms of nutrients, such as glucose or glutamine, and then assessing labelling of downstream metabolic intermediates.
- Jumonji-domain-containing histone demethylases
Members of the family of α-ketoglutarate-dependent dioxygenases that contain a common structural domain that facilitates protein demethylation.
A non-selective form of endocytosis in which cells engulf extracellular fluid and other macromolecular cargo.
- Myeloid cells
Bone-marrow-derived cells of a common lineage, including monocytes, macrophages, dendritic cells and granulocytes.
- Receptor-mediated endocytosis
A process by which cell surface receptors and their ligands are internalized in a clathrin-dependent fashion.
- Stromal cells
Cells that functionally or architecturally support tissues throughout the body.
- Tumour initiation
The process in which a cell (‘cell of origin’) acquires the ability to self-renew, propagate and withstand elimination to eventually give rise to a tumour.
- Tumour microenvironment
(TME). The cells and molecules that comprise the local ecosystem of a tumour, including the cancer cells, stromal and immune cells and blood vessels, as well as the interstitial fluid and any proteins, metabolites or other molecules therein.
- Tumour progression
The evolution of a tumour towards increased malignancy; can refer to increases in tumour size, stage or dissemination to new sites for metastatic growth.
- Tumour-associated stem cells
A subset of cancer cells within a tumour that display capacity for self-renewal and differentiation; these cells are often associated with therapy resistance and tumour aggressiveness.
About this article
Cite this article
Brunner, J.S., Finley, L.W.S. Metabolic determinants of tumour initiation. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00773-5