Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment

Abstract

Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: KRAS* rewires cancer cell metabolism.
Fig. 2: KRAS* synergizes with co-occurring mutations to direct metabolism.
Fig. 3: Tissue specific metabolism hijacked by KRAS*.
Fig. 4: Interactions in the KRAS* TME.

References

  1. 1.

    Mo, S. P., Coulson, J. M. & Prior, I. A. RAS variant signalling. Biochem. Soc. Trans. 46, 1325–1332 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Sanchez-Vega, F. et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321–337.e310 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Ledford, H. Cancer: the Ras renaissance. Nature 520, 278–280 (2015).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Cox, A. D., Der, C. J. & Philips, M. R. Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin. Cancer Res. 21, 1819–1827 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Li, S., Balmain, A. & Counter, C. M. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat. Rev. Cancer 18, 767–777 (2018).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Zafra, M. P. et al. An in vivo Kras allelic series reveals distinct phenotypes of common oncogenic variants. Cancer Discov. 10, 1654–1671 (2020). This study generated mice harbouring a series of Kras mutations in the pancreas or lung and reported significant differences in transformative capabilities and responses to treatments.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Serebriiskii, I. G. et al. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat. Commun. 10, 3722 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Collins, M. A. et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Skoulidis, F. & Heymach, J. V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat. Rev. Cancer 19, 495–509 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Crawford, H. C., Pasca di Magliano, M. & Banerjee, S. Signaling networks that control cellular plasticity in pancreatic tumorigenesis, progression, and metastasis. Gastroenterology 156, 2073–2084 (2019).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Peddareddigari, V. G., Wang, D. & Dubois, R. N. The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron. 3, 149–166 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Zeitouni, D., Pylayeva-Gupta, Y., Der, C. J. & Bryant, K. L. KRAS mutant pancreatic cancer: no lone path to an effective treatment. Cancers 8, 45 (2016).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  21. 21.

    Bryant, K. L., Mancias, J. D., Kimmelman, A. C. & Der, C. J. KRAS: feeding pancreatic cancer proliferation. Trends Biochem. Sci. 39, 91–100 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Kerr, E. M., Gaude, E., Turrell, F. K., Frezza, C. & Martins, C. P. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531, 110–113 (2016). This study demonstrates that a gain in copy number of mutant Kras late in lung tumour progression results in substantial metabolic rewiring.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). This study illustrates how oncogenic Kras signalling regulates metabolism through MAPK signalling and MYC activity in pancreatic cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Pupo, E., Avanzato, D., Middonti, E., Bussolino, F. & Lanzetti, L. KRAS-driven metabolic rewiring reveals novel actionable targets in cancer. Front. Oncol. 9, 848 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Gaglio, D. et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 7, 523 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Kerr, E. M. & Martins, C. P. Metabolic rewiring in mutant Kras lung cancer. FEBS J. 285, 28–41 (2018).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Hutton, J. E. et al. Oncogenic KRAS and BRAF drive metabolic reprogramming in colorectal cancer. Mol. Cell Proteom. 15, 2924–2938 (2016).

    CAS  Article  Google Scholar 

  29. 29.

    Aguilera, O. et al. Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer. Oncotarget 7, 47954–47965 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Iwamoto, M. et al. Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. J. Nucl. Med. 55, 2038–2044 (2014).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Kawada, K. et al. Relationship between 18F-fluorodeoxyglucose accumulation and KRAS/BRAF mutations in colorectal cancer. Clin. Cancer Res. 18, 1696 (2012).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Amendola, C. R. et al. KRAS4A directly regulates hexokinase 1. Nature 576, 482–486 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Wang, H. et al. Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer Cell Int. 16, 9 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Kim, J. et al. The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer. Nat. Metab. https://doi.org/10.1038/s42255-020-00316-0 (2020). This study identifies loss of LKB1 in KRAS* lung cancer results in an increased dependency on the hexosamine biosynthesis pathway, providing a prime example for how co-occurring mutations cooperate with KRAS* to direct metabolism.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Ali, E. S. et al. ERK2 phosphorylates PFAS to mediate posttranslational control of de novo purine synthesis. Mol. Cell 78, 1178–1191.e1176 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Mattaini, K. R., Sullivan, M. R. & Vander Heiden, M. G. The importance of serine metabolism in cancer. J. Cell Biol. 214, 249–257 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Maddocks, O. D. K. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Xie, H. et al. Targeting lactate dehydrogenase–a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 19, 795–809 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    McCleland, M. L. et al. Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin. Cancer Res. 19, 773–784 (2013).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kerk, S. A. et al. The pancreatic tumor microenvironment buffers redox imbalance imposed by disrupted mitochondrial metabolism. Preprint at bioRxiv https://doi.org/10.1101/2020.08.07.238766 (2020).

    Article  Google Scholar 

  42. 42.

    Baek, G. et al. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 9, 2233–2249 (2014).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Graziano, F. et al. Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer. Pharmacogenomics J. 17, 258–264 (2017).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Martinez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Vasan, K., Werner, M. & Chandel, N. S. Mitochondrial metabolism as a target for cancer therapy. Cell Metab. 32, 341–352 (2020).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Kong, H. & Chandel, N. S. Regulation of redox balance in cancer and T cells. J. Biol. Chem. 293, 7499–7507 (2018).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Chandel, N. S. Evolution of mitochondria as signaling organelles. Cell Metab. 22, 204–206 (2015).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Humpton, T. J. et al. Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer. Cancer Discov. 9, 1268–1287 (2019). This study finds that in mouse models of PDA KRAS* regulates mitochondrial dynamics and function to optimize ROS signalling and maximize bioenergetic programmes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Sullivan, L. B. & Chandel, N. S. Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2, 17 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010). This is among the first studies to illustrate how mutant Kras influences metabolism.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Chauhan, S. S. et al. PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer. Oncogene 39, 2597–2611 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Kashatus, J. A. et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol. Cell 57, 537–551 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Yu, M. et al. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight https://doi.org/10.1172/jci.insight.126915 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    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 extensively details the differential utilization of glucose and glutamine in lung cancer cells between in vitro and in vivo models.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Miyo, M. et al. Metabolic adaptation to nutritional stress in human colorectal cancer. Sci. Rep. 6, 38415 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Mayers, J. R. & Vander Heiden, M. G. Famine versus feast: understanding the metabolism of tumors in vivo. Trends Biochem. Sci. 40, 130–140 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Wong, C. C. et al. SLC25A22 promotes proliferation and survival of colorectal cancer cells With KRAS mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Gastroenterology 151, 945–960 e946 (2016).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Toda, K. et al. Metabolic alterations caused by KRAS mutations in colorectal cancer contribute to cell adaptation to glutamine depletion by upregulation of asparagine synthetase. Neoplasia 18, 654–665 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Halbrook, C. J. et al. Clonal heterogeneity supports mitochondrial metabolism in pancreatic cancer. Preprint at bioRxiv https://doi.org/10.1101/2020.05.15.098368 (2020).

    Article  Google Scholar 

  65. 65.

    Gwinn, D. M. et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33, 91–107.e106 (2018). This study shows that under nutrient deprivation, signalling downstream of KRAS* in KEAP1-deficient lung cancer increases asparagine production and that these tumours are sensitive to asparagine depletion via asparaginase.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Bott, A. J. et al. Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Rep. 29, 1287–1298.e1286 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013). This early work engineers normal cell types to express KRAS* and identifies that KRAS* upregulates macropinocytosis to non-specifically consume extracellular nutrients.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Ramirez, C., Hauser, A. D., Vucic, E. A. & Bar-Sagi, D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. Nature 576, 477–481 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Hodakoski, C. et al. Rac-mediated macropinocytosis of extracellular protein promotes glucose independence in non-small cell lung cancer. Cancers https://doi.org/10.3390/cancers11010037 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    King, B., Araki, J., Palm, W. & Thompson, C. B. Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis. Genes Dev. 34, 1345–1358 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Palm, W., Araki, J., King, B., DeMatteo, R. G. & Thompson, C. B. Critical role for PI3-kinase in regulating the use of proteins as an amino acid source. Proc. Natl Acad. Sci. USA 114, E8628–E8636 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Zhang, Y. & Commisso, C. Macropinocytosis in cancer: a complex signaling network. Trends Cancer 5, 332–334 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Lee, S. W. et al. EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis. Dev. Cell 50, 381–392 e385 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Hobbs, G. A. et al. Atypical KRAS(G12R) mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 10, 104–123 (2020).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Kimmelman, A. C. & White, E. Autophagy and tumor metabolism. Cell Metab. 25, 1037–1043 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Perera, R. M. et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Perera, R. M. & Bardeesy, N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 5, 1247–1261 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Yang, A. et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 8, 276–287 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Yang, S. et al. Autophagy inhibition dysregulates TBK1 signaling and promotes pancreatic inflammation. Cancer Immunol. Res. 4, 520–530 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011). This work provides evidence that mutant RAS upregulates autophagy to provide nutrients and sustain metabolic programmes during acute nutrient stress.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Amaravadi, R. K., Kimmelman, A. C. & Debnath, J. Targeting autophagy in cancer: recent advances and future directions. Cancer Discov. 9, 1167–1181 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    White, E. Exploiting the bad eating habits of Ras-driven cancers. Genes Dev. 27, 2065–2071 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Guo, J. Y. et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 30, 1704–1717 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Bryant, K. L. et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 25, 628–640 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    White, E. Blockade of RAF and autophagy is the one-two punch to take out Ras. Proc. Natl Acad. Sci. USA 116, 3965–3967 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Poillet-Perez, L. et al. Autophagy maintains tumour growth through circulating arginine. Nature 563, 569–573 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Currie, E. et al. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Singh, A. et al. De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer. FASEB J. https://doi.org/10.1096/fj.201800204 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Gouw, A. M. et al. Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc. Natl Acad. Sci. USA 114, 4300–4305 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Zaytseva, Y. Y. et al. Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration. Oncotarget 6, 18891–18904 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Padanad, M. S. et al. Fatty acid oxidation mediated by acyl-CoA synthetase long chain 3 is required for mutant KRAS lung tumorigenesis. Cell Rep. 16, 1614–1628 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Guillaumond, F. et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 112, 2473–2478 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Rozeveld, C. N., Johnson, K. M., Zhang, L. & Razidlo, G. L. KRAS controls pancreatic cancer cell lipid metabolism and invasive potential through the lipase HSL. Cancer Res. 80, 4932 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Phelps, R. A. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137, 623–634 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Wong, C. C. et al. In colorectal cancer cells with mutant KRAS, SLC25A22-mediated glutaminolysis reduces DNA demethylation to increase WNT signaling, stemness, and drug resistance. Gastroenterology https://doi.org/10.1053/j.gastro.2020.08.016 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC, Metabolism, and Cancer. Cancer Discov. 5, 1024 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Sansom, O. J. et al. Myc deletion rescues Apc deficiency in the small intestine. Nature 446, 676–679 (2007).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Satoh, K. et al. Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1710366114 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Venkateswaran, N. et al. MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer. Genes Dev. 33, 1236–1251 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Soucek, L. et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 27, 504–513 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Sodir, N. M. MYC instructs and maintains pancreatic adenocarcinoma phenotype. Cancer Discov.10, 588–607 (2020).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778.e764 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Boutin, A. T. et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 31, 370–382 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Feng, Y. et al. Mutant kras promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology 141, 1003–1013.e1010 (2011).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Hinoi, T. et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 67, 9721 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Tang, J. et al. Trp53 null and R270H mutant alleles have comparable effects in regulating invasion, metastasis, and gene expression in mouse colon tumorigenesis. Lab. Invest. 99, 1454–1469 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Murray, C. W. et al. An LKB1-SIK axis suppresses lung tumor growth and controls differentiation. Cancer Discov. 9, 1590–1605 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Hollstein, P. E. et al. The AMPK-related kinases SIK1 and SIK3 mediate key tumor-suppressive effects of LKB1 in NSCLC. Cancer Discov. 9, 1606–1627 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Faubert, B. et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1alpha. Proc. Natl Acad. Sci. USA 111, 2554–2559 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Eichner, L. J. et al. Genetic analysis reveals AMPK is required to support tumor growth in murine kras-dependent lung cancer models. Cell Metab. 29, 285–302 e287 (2019).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Liu, G. & Summer, R. Cellular metabolism in lung health and disease. Annu. Rev. Physiol. 81, 403–428 (2019).

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Bhatt, V. et al. Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis. Genes Dev. 33, 150–165 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). This work shows that lung tumours with KRAS* and LKB1 deficiency utilize an unconventional pathway to recycle nitrogen for use in vital nucleotide production.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Su, G. H. et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am. J. Pathol. 154, 1835–1840 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Morton, J. P. et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 139, 586–597.e5976 (2010).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Tierney, D. F. Lung metabolism and biochemistry. Annu. Rev. Physiol. 36, 209–231 (1974).

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Fisher, A. B. Intermediary metabolism of the lung. Env. Health Perspect. 55, 149–158 (1984).

    CAS  Article  Google Scholar 

  132. 132.

    Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Ghergurovich, J. M. et al. Glucose-6-phosphate dehydrogenase is not essential for K-ras–driven tumor growth or metastasis. Cancer Res. 80, 3820 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Galan-Cobo, A. et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Cancer Res. 79, 3251–3267 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Sayin, V. I. et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. eLife https://doi.org/10.7554/eLife.28083 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Morris, J. P. T. et al. alpha-Ketoglutarate links p53 to cell fate during tumour suppression. Nature 573, 595–599 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Ju, H. Q. et al. Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Nat. Commun. 8, 14437 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Dey, P. et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature 542, 119–123 (2017). This study identifies that in PDA ME2 is near the SMAD4 locus and is lost concurrently with SMAD4 deletion, conferring a unique dependency for PDA on ME3 activity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    CAS  Article  Google Scholar 

  147. 147.

    Berkers, C. R., Maddocks, O. D. K., Cheung, E. C., Mor, I. & Vousden, K. H. Metabolic regulation by p53 family members. Cell metabolism 18, 617–633 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Ortiz-Prado, E., Dunn, J. F., Vasconez, J., Castillo, D. & Viscor, G. Partial pressure of oxygen in the human body: a general review. Am. J. Blood Res. 9, 1–14 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Albenberg, L. et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 147, 1055–1063 e1058 (2014).

    PubMed  Article  Google Scholar 

  150. 150.

    Shay, J. E. & Celeste Simon, M. Hypoxia-inducible factors: crosstalk between inflammation and metabolism. Semin. Cell Dev. Biol. 23, 389–394 (2012).

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    McGettrick, A. F. & O’Neill, L. A. J. The role of HIF in immunity and inflammation. Cell Metab. 32, 524–536 (2020).

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Schofield, C. J. & Ratcliffe, P. J. Signalling hypoxia by HIF hydroxylases. Biochem. Biophys. Res. Commun. 338, 617–626 (2005).

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Xie, L. et al. Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation. Mol. Cell Biol. 34, 3013–3023 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. 156.

    Manresa, M. C. & Taylor, C. T. Hypoxia inducible factor (HIF) hydroxylases as regulators of intestinal epithelial barrier function. Cell Mol. Gastroenterol. Hepatol. 3, 303–315 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Gilsing, A. M. et al. Dietary heme iron and the risk of colorectal cancer with specific mutations in KRAS and APC. Carcinogenesis 34, 2757–2766 (2013).

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Chun, S. Y. et al. Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1alpha and HIF-2alpha target genes. Mol. Cancer 9, 29 (2010).

    Article  CAS  Google Scholar 

  159. 159.

    Zeng, M., Kikuchi, H., Pino, M. S. & Chung, D. C. Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells. PLoS ONE 5, e10966 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. 160.

    Richard, D. E., Berra, E., Gothie, E., Roux, D. & Pouyssegur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 (1999).

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Mylonis, I. et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J. Biol. Chem. 281, 33095–33106 (2006).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Kikuchi, H., Pino, M. S., Zeng, M., Shirasawa, S. & Chung, D. C. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer. Cancer Res. 69, 8499–8506 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Dang, D. T. et al. Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res. 66, 1684–1936 (2006).

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Taylor, M. et al. Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044–2055 (2011).

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Schwartz, A. J. et al. Hepatic hepcidin/intestinal HIF-2alpha axis maintains iron absorption during iron deficiency and overload. J. Clin. Invest. 129, 336–348 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Xue, X. et al. Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis. Cell Metab. 24, 447–461 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Xue, X. et al. Hypoxia-inducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 72, 2285–2293 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Stockwell, B. R. & Jiang, X. The chemistry and biology of ferroptosis. Cell Chem. Biol. 27, 365–375 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Stockwell, B. R., Jiang, X. & Gu, W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 30, 478–490 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Hui, S. et al. Quantitative fluxomics of circulating metabolites. Cell Metab. 32, 676–688 e674 (2020).

    CAS  Article  Google Scholar 

  173. 173.

    Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. 174.

    Bailey, J. M. et al. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene 35, 4282–4288 (2016).

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467.e456 (2018).

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Jang, C. et al. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30, 594–606 e593 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Li, J. T. et al. BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma. Nat. Cell Biol. 22, 167–174 (2020).

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    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 work posits that lung and not pancreas tumours depend on BCAA metabolism, which illustrates that the environmental context and co-occurring mutations are also pivotal in dictating tumour metabolism.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Zhu, Z. et al. Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours. Nat. Metab. 2, 775–792 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Nelson, B. S. et al. Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy. Cancer Metab. 8, 1 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Chowdhry, S. et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 569, 570–575 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Lyssiotis, C. A. & Kimmelman, A. C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27, 863–875 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Schworer, S., Vardhana, S. A. & Thompson, C. B. Cancer metabolism drives a stromal regenerative response. Cell Metab. 29, 576–591 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Olenchock, B. A., Rathmell, J. C. & Vander Heiden, M. G. Biochemical underpinnings of immune cell metabolic phenotypes. Immunity 46, 703–713 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Leone, R. D. & Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20, 516–531 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Andrejeva, G. & Rathmell, J. C. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 26, 49–70 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    MacCarthy-Morrogh, L. & Martin, P. The hallmarks of cancer are also the hallmarks of wound healing. Sci. Signal. 13, eaay8690 (2020).

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 910–920 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    di Magliano, M. P. & Logsdon, C. D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 144, 1220–1229 (2013).

    PubMed  Article  CAS  Google Scholar 

  192. 192.

    Georges, L. M., Verset, L., Zlobec, I., Demetter, P. & De Wever, O. Impact of the microenvironment on tumour budding in colorectal cancer. Adv. Exp. Med. Biol. 1110, 101–111 (2018).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Abe, Y. & Tanaka, N. The hedgehog signaling networks in lung cancer: the mechanisms and roles in tumor progression and implications for cancer therapy. Biomed. Res. Int. 2016, 7969286 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. 194.

    Lee, K. E. et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. 6, 256–269 (2016).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Pylayeva-Gupta, Y. et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016).

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    DeNardo, D. G. et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Dey, P. et al. Oncogenic KRAS-driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment. Cancer Discov. 10, 608–625 (2020). This work shows how cytokine signalling mediated by KRAS* from PDA cells to the immune compartment results in a compensatory mechanism by which immune signalling promotes glycolysis in the cancer cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 e974 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Zhang, D. et al. Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. Cell Rep. 10, 1335–1348 (2015).

    PubMed  Article  CAS  Google Scholar 

  200. 200.

    Halestrap, A. P. The monocarboxylate transporter family–structure and functional characterization. IUBMB Life 64, 1–9 (2012).

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Halestrap, A. P. & Wilson, M. C. The monocarboxylate transporter family–role and regulation. IUBMB Life 64, 109–119 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Hutcheson, J. et al. Immunologic and metabolic features of pancreatic ductal adenocarcinoma define prognostic subtypes of disease. Clin. Cancer Res. 22, 3606–3617 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. 203.

    Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Harmon, C. et al. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis. Cancer Immunol. Res. 7, 335–346 (2019).

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Zhao, Y. et al. Colorectal cancers utilize glutamine as an anaplerotic substrate of the TCA cycle in vivo. Sci. Rep. 9, 19180 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Sugiura, A. & Rathmell, J. C. Metabolic barriers to T cell function in tumors. J. Immunol. 200, 400–407 (2018).

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Smith, C. et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2, 722–735 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Hsu, Y. L. et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7, 27584–27598 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Brandacher, G. et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12, 1144–1151 (2006).

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Witkiewicz, A. K. et al. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Am. Coll. Surg. 208, 781–789 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep. 13, 412–424 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Sadik, A. et al. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell 182, 1252–1270.e1234 (2020).

    CAS  PubMed  Article  Google Scholar 

  214. 214.

    Szefel, J., Danielak, A. & Kruszewski, W. J. Metabolic pathways of L-arginine and therapeutic consequences in tumors. Adv. Med. Sci. 64, 104–110 (2019).

    PubMed  Article  Google Scholar 

  215. 215.

    Zhang, Y. et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. 10, 422–439 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Chaudhri, V. K. et al. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol. Cancer Res. 11, 579–592 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. 217.

    Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  219. 219.

    Zahalka, A. H. & Frenette, P. S. Nerves in cancer. Nat. Rev. Cancer 20, 143–157 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. 220.

    Banh, R. S. et al. Neurons release serine to support mRNA translation in pancreatic cancer. Cell https://doi.org/10.1016/j.cell.2020.10.016 (2020).

    Article  PubMed  Google Scholar 

  221. 221.

    Manzo, T. et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J. Exp. Med. https://doi.org/10.1084/jem.20191920 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014). This study discovers that certain PDA cells are resistant to extinguished KRAS* signalling through increased mitochondrial metabolism, demonstrating potential metabolic resistance mechanisms to targeting of KRAS*.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    Hou, P. et al. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer. Cancer Discov. 10, 1058–1077 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185–197 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    Tanaka, N. et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0365 (2021).

    Article  PubMed  Google Scholar 

  226. 226.

    Muzumdar, M. D. et al. Survival of pancreatic cancer cells lacking KRAS function. Nat. Commun. 8, 1090 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  227. 227.

    Chen, P.-Y. et al. Adaptive and reversible resistance to Kras inhibition in pancreatic cancer cells. Cancer Res. 78, 985 (2018).

    CAS  PubMed  Article  Google Scholar 

  228. 228.

    Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e517 (2018).

    CAS  PubMed  Article  Google Scholar 

  229. 229.

    Yao, W. et al. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature 568, 410–414 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Shackelford, D. B. et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Liu, Y. et al. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov. 3, 870 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. 232.

    LeBoeuf, S. E. et al. Activation of oxidative stress response in cancer generates a druggable dependency on exogenous non-essential amino acids. Cell Metab. 31, 339–350.e334 (2020).

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Yan, Y. et al. The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer. J. Exp. Clin. Cancer Res. 38, 171 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  235. 235.

    Dalin, S. et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res. 79, 5723–5733 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. 236.

    Halbrook, C. J. et al. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab. 29, 1390–1399 e1396 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  238. 238.

    Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science 362, eaar3593 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  239. 239.

    Brahmer, J. R. et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science https://doi.org/10.1126/science.aav2588 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Ma, E. H. et al. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 51, 856–870 e855 (2019).

    CAS  Article  Google Scholar 

  242. 242.

    Balmer, M. L. et al. Memory CD8+ T cells balance pro- and anti-inflammatory activity by reprogramming cellular acetate handling at sites of infection. Cell Metab. 32, 457–467.e455 (2020).

    CAS  PubMed  Article  Google Scholar 

  243. 243.

    Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e844 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. 245.

    Rizvi, H. et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol. 36, 633–641 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Arbour, K. C. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 334 (2018).

    CAS  PubMed  Article  Google Scholar 

  247. 247.

    Halbrook, C. J., Pasca di Magliano, M. & Lyssiotis, C. A. Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G27–G35 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  248. 248.

    Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Zhu, X. G. et al. Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells. Cell Metab. https://doi.org/10.1016/j.cmet.2020.10.017 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).

    CAS  PubMed  Article  Google Scholar 

  251. 251.

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    CAS  PubMed  Article  Google Scholar 

  252. 252.

    Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    CAS  PubMed  Article  Google Scholar 

  253. 253.

    Xu, X. et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 4910–4915 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  254. 254.

    Mainardi, S. et al. Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma. Proc. Natl Acad. Sci. USA 111, 255–260 (2014).

    CAS  PubMed  Article  Google Scholar 

  255. 255.

    Sutherland, K. D. et al. Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma. Proc. Natl Acad. Sci. USA 111, 4952–4957 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).

    CAS  PubMed  Article  Google Scholar 

  257. 257.

    Best, S. A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab. 27, 935–943.e934 (2018).

    CAS  PubMed  Article  Google Scholar 

  258. 258.

    Best, S. A. et al. Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma. Nat. Commun. 10, 4190 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  259. 259.

    Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  260. 260.

    De La O, J.-P. et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.0810111105 (2008).

    Article  Google Scholar 

  261. 261.

    Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.0810097105 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  262. 262.

    Litvak, Y., Byndloss, M. X. & Baumler, A. J. Colonocyte metabolism shapes the gut microbiota. Science https://doi.org/10.1126/science.aat9076 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  263. 263.

    Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    McNabney, S. M. & Henagan, T. M. Short chain fatty acids in the colon and peripheral tissues: a focus on butyrate, colon cancer, obesity and insulin resistance. Nutrients https://doi.org/10.3390/nu9121348 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  265. 265.

    Leinwand, J. & Miller, G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat. Immunol. 21, 1152–1159 (2020).

    CAS  PubMed  Article  Google Scholar 

  266. 266.

    Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  267. 267.

    Jin, C. et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell 176, 998–1013.e1016 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  268. 268.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  Article  Google Scholar 

  269. 269.

    Tsay, J. J. et al. Airway microbiota is associated with upregulation of the PI3K pathway in lung cancer. Am. J. Respir. Crit. Care Med. 198, 1188–1198 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  270. 270.

    Segal, L. N. et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat. Microbiol. 1, 16031 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

S.A.K. is supported by NIH award F31CA247457. T.P. is supported by NIH grants R37CA222504 and R01CA227649 and American Cancer Society Research Scholar Grant RSG-17-200-01—TBE. Y.M.S. is supported by NIH grants R01CA245546 and R01CA148828. C.A.L. is supported by NIH grants R37CA237421, R01CA248160 and R01CA244931.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Costas A. Lyssiotis.

Ethics declarations

Competing interests

T.P. has received honoraria and consulting fees from Calithera Biosciences and research support from Dracen Pharmaceuticals and Agios Pharmaceuticals. C.A.L. has received consulting fees from Astellas Pharmaceuticals and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer and targeting the GOT1 pathway as a therapeutic approach. Y.M.S. and S.A.K. have no competing interests to declare.

Additional information

Peer review information

Nature Reviews Cancer thanks C. Der, P. Dey, J.Y. Guo and Ö. Yilmaz 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.

Glossary

Glycolysis

The enzymatic oxidation of glucose to pyruvate, which produces energy and carbon for bioenergetic and biosynthetic processes.

Oxidation state

In cellular metabolism, the availability of electron acceptors as determined by the breakdown or production of metabolites.

Mitophagy

Selective targeting and degradation of mitochondria, often those that are defective or excessive.

Electron transport chain

(ETC). A series of electron-accepting enzymes embedded in the inner mitochondrial membrane responsible for producing the proton-motive force needed for energy production.

Reactive oxygen species

(ROS). Small, oxygen-containing molecules that are highly reactive due to the electron-accepting nature of oxygen.

Mitochondrial fission or mitochondrial fusion

A process by which mitochondria are combined (fusion) or divided into smaller fragments (fission).

Glutaminolysis

The enzymatic breakdown of the amino acid glutamine.

Tricarboxylic acid (TCA) cycle

A series of mitochondrial enzymatic reactions that oxidize metabolic intermediates to produce reducing equivalents that drive the electron transport chain and intermediates for the synthesis of lipids and amino acids.

Anaplerosis

Replenishment of tricarboxylic acid cycle intermediates.

Macropinocytosis

Regulated, non-specific engulfment of the extracellular space by the cellular plasma membrane to obtain nutrients.

Autophagy

Degradation of intracellular metabolites and organelles to eliminate damaged cellular components and/or provide basic metabolic building blocks.

Urea cycle

A series of chemical reactions involving nitrogen-containing metabolites essential for recycling nitrogen or excreting toxic ammonia waste as urea.

Glutathione

(GSH). Cellular antioxidant composed of glutamate, cysteine and glycine important for quenching damaging reactive oxygen species levels.

Cystine

The water-soluble dimer of the amino acid cysteine.

System XC

Amino acid antiporter system that exchanges glutamate for cystine.

Oxidative phosphorylation

Oxygen-dependent process by which the proton-motive force between the inner mitochondrial membrane space and matrix is used to generate ATP.

Hypoxia-inducible factors

(HIFs). Transcription factors, stabilized under conditions of low oxygen levels, targeting the promoters of genes containing hypoxia response elements.

Ferroptosis

An oxidative, iron-dependent form of programmed cell death.

Isotope tracing

Application of metabolites in which stable isotopes are incorporated to follow the metabolism or fate of a given nutrient (for example via mass spectroscopy-based metabolomics).

Acinar–ductal metaplasia

The morphological and transcriptional programmes by which acinar cells dedifferentiate into ductal cells in response to injury or oncogenic stress.

Pyrimidine synthesis

The metabolic pathway producing the nucleotides uridine, cytidine and thymidine.

Microsatellite instability

(MSI). An inherent propensity for genomic mutations caused by malfunctioning DNA repair machinery.

Deamidases

Enzymes that catalyse the removal of amido groups.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kerk, S.A., Papagiannakopoulos, T., Shah, Y.M. et al. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat Rev Cancer 21, 510–525 (2021). https://doi.org/10.1038/s41568-021-00375-9

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing