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Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer

British Journal of Cancer volume 124, pages 1902–1911 (2021)Cite this article

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Abstract

Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. A developmental programme known as epithelial-to-mesenchymal transition (EMT) plays a critical role during metastasis, promoting the loss of polarity and cell–cell adhesion and the acquisition of motile, stem-cell characteristics. Cells undergoing EMT or the reverse mesenchymal-to-epithelial transition (MET) are often associated with metabolic changes, as the change in phenotype often correlates with a different balance of proliferation versus energy-intensive migration. Extensive crosstalk occurs between metabolism and EMT, but how this crosstalk leads to coordinated physiological changes is still uncertain. The elusive connection between metabolism and EMT compromises the efficacy of metabolic therapies targeting metastasis. In this review, we aim to clarify the causation between metabolism and EMT on the basis of experimental studies, and propose integrated theoretical–experimental efforts to better understand the coupled decision-making of metabolism and EMT.

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Fig. 1: Crosstalk between EMT and metabolism in cancer.
Fig. 2: Hypothetical coupling of EMT and metabolic reprogramming during the acquisition of stemness.
Fig. 3: A systematic pipeline to elucidate the connection between EMT and metabolic reprogramming.

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References

  1. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Burger, G. A., Danen, E. H. J. & Beltman, J. B. Deciphering epithelial-mesenchymal transition regulatory networks in cancer through computational approaches. Front. Oncol. 7, 162 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tripathi, S., Levine, H. & Jolly, M. K. The physics of cellular decision making during epithelial-mesenchymal transition. Annu. Rev. Biophys. 49, 1–18 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Weinhouse, S., Warburg, O., Burk, D. & Schade, A. L. On respiratory impairment in cancer cells. Science 124, 267–272 (1956).

    Article  CAS  PubMed  Google Scholar 

  6. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shyh-Chang, N. & Ng, H.-H. The metabolic programming of stem cells. Genes Dev. 31, 336–346 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bhattacharya, D., Azambuja, A. P. & Simoes-Costa, M. Metabolic reprogramming promotes neural crest migration via yap/tead signaling. Dev. Cell 53, 199–211.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Krapf, S. A., Lund, J., Lundkvist, M., Dale, M. G., Nyman, T. A., Thoresen, G. H. et al. Pancreatic cancer cells show lower oleic acid oxidation and their conditioned medium inhibits oleic acid oxidation in human myotubes. Pancreatology 20, 676–682 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Zu, X. L. & Guppy, M. Cancer metabolism: facts, fantasy, and fiction. Biochem. Biophys. Res. Commun. 313, 459–465 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Jia, D., Park, J. H., Jung, K. H., Levine, H. & Kaipparettu, B. A. Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cells 7, 21 (2018).

  12. Porporato, P. E., Payen, V. L., Pérez-Escuredo, J., De Saedeleer, C. J., Danhier, P., Copetti, T. et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 8, 754–766 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. LeBleu, V. S., O’Connell, J. T., Gonzalez Herrera, K. N., Wikman, H., Pantel, K., Haigis, M. C. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dupuy, F., Tabariès, S., Andrzejewski, S., Dong, Z., Blagih, J., Annis, M. G. et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22, 577–589 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Park, J. H., Vithayathil, S., Kumar, S., Sung, P.-L., Dobrolecki, L. E., Putluri, V. et al. Fatty acid oxidation-driven Src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep. 14, 2154–2165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pastushenko, I., Brisebarre, A., Sifrim, A., Fioramonti, M., Revenco, T., Boumahdi, S. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Lu, M., Jolly, M. K., Levine, H., Onuchic, J. N. & Ben-Jacob, E. MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination. Proc. Natl. Acad. Sci. USA 110, 18144–18149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jolly, M. K., Boareto, M., Huang, B., Jia, D., Lu, M., Ben-Jacob, E. et al. Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Front. Oncol. 5, 155 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jolly, M. K., Tripathi, S. C., Jia, D., Mooney, S. M., Celiktas, M., Hanash, S. M. et al. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 7, 27067–27084 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jia, D., Lu, M., Jung, K. H., Park, J. H., Yu, L., Onuchic, J. N. et al. Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways. Proc. Natl Acade. Sci. USA 116, 3909–3918 (2019).

    Article  CAS  Google Scholar 

  21. Commander, R., Wei, C., Sharma, A., Mouw, J. K., Burton, L. J., Summerbell, E. et al. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nat. Commun. 11, 1533 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jiang, L., Xiao, L., Sugiura, H., Huang, X., Ali, A., Kuro-o, M. et al. Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. Oncogene 34, 3908–3916 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Tam, W. L. & Weinberg, R. A. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Medicine 19, 1438–1449 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rodríguez-García, A., Samsó, P., Fontova, P., Simon-Molas, H., Manzano, A., Castaño, E. et al. TGF-β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells. FEBS J. 284, 3437–3454 (2017).

    Article  PubMed  CAS  Google Scholar 

  25. Corbet, C., Bastien, E., Santiago de Jesus, J. P., Dierge, E., Martherus, R., Vander Linden, C. et al. TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nat. Commun. 11, 454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yalcin, A., Solakoglu, T. H., Ozcan, S. C., Guzel, S., Peker, S., Celikler, S. et al. 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for transforming growth factor β1-enhanced invasion of Panc1 cells in vitro. Biochem. Biophys. Res. Commun. 484, 687–693 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Liu, M., Quek, L.-E., Sultani, G. & Turner, N. Epithelial-mesenchymal transition induction is associated with augmented glucose uptake and lactate production in pancreatic ductal adenocarcinoma. Cancer Metab 4, 19 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jolly, M. K., Huang, B., Lu, M., Mani, S. A., Levine, H., Ben-Jacob, E. et al. Towards elucidating the connection between epithelial–mesenchymal transitions and stemness. J. R. Soc. Interface 11, 20140962 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lee, S., Lee, J.-S., Seo, J., Lee, S.-H., Kang, J. H., Song, J. et al. Targeting mitochondrial oxidative phosphorylation abrogated irinotecan resistance in NSCLC. Sci. Rep. 8, 15707 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kang, H. M., Ahn, S. H., Choi, P., Ko, Y.-A., Han, S. H., Chinga, F. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Dong, C., Yuan, T., Wu, Y., Wang, Y., Fan, T. W. M., Miriyala, S. et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23, 316–331 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Røsland, G. V., Dyrstad, S. E., Tusubira, D., Helwa, R., Tan, T. Z., Lotsberg, M. L. et al. Epithelial to mesenchymal transition (EMT) is associated with attenuation of succinate dehydrogenase (SDH) in breast cancer through reduced expression of. Cancer Metab 7, 6 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zancan, P., Sola-Penna, M. & Furtado, C. M. & Da Silva, D. Differential expression of phosphofructokinase-1 isoforms correlates with the glycolytic efficiency of breast cancer cells. Mol. Genet. Metab. 100, 372–378 (2010)..

  35. Yang, L., Hou, Y., Yuan, J., Tang, S., Zhang, H., Zhu, Q. et al. Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways. Oncotarget 6, 25755–25769 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Krebs, A. M., Mitschke, J., Lasierra Losada, M., Schmalhofer, O., Boerries, M., Busch, H. et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Jia, D., Jolly, M. K., Tripathi, S. C., Den Hollander, P., Huang, B., Lu, M. et al. Distinguishing mechanisms underlying EMT tristability. Cancer Converg 1, 2 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Masin, M., Vazquez, J., Rossi, S., Groeneveld, S., Samson, N., Schwalie, P. C. et al. GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer. Cancer Metab 2, 11 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kim, N. H., Cha, Y. H., Lee, J., Lee, S.-H., Yang, J. H., Yun, J. S. et al. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nat. Commun. 8, 14374 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Viswanathan, V. S., Ryan, M. J., Dhruv, H. D., Gill, S., Eichhoff, O. M., Seashore-Ludlow, B. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mathow, D., Chessa, F., Rabionet, M., Kaden, S., Jennemann, R., Sandhoff, R. et al. Zeb1 affects epithelial cell adhesion by diverting glycosphingolipid metabolism. EMBO Rep. 16, 321–331 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Siddiqui, A., Vazakidou, M. E., Schwab, A., Napoli, F., Fernandez-Molina, C., Rapa, I. et al. Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells. J. Pathol. 242, 221–233 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Lee, J., You, J. H., Kim, M.-S. & Roh, J.-L. Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer. Redox Biol 37, 101697 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Battistelli, C., Cicchini, C., Santangelo, L., Tramontano, A., Grassi, L., Gonzalez, F. J. et al. The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene 36, 942–955 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Korpal, M., Lee, E. S., Hu, G. & Kang, Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910–14914 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, Y., Liu, Z., Yao, B., Dou, C., Xu, M., Xue, Y. et al. Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma. Tumor Biol. 37, 11429–11441 (2016).

    Article  CAS  Google Scholar 

  48. Kaller, M., Liffers, S.-T., Oeljeklaus, S., Kuhlmann, K., Röh, S. Hoffmann, R. et al. Genome-wide characterization of miR-34a induced changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis. Mol. Cell. Proteomics 10, M111.010462 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Yuan, D., Zheng, S., Wang, L., Li, J., Yang, J., Wang, B. et al. MiR-200c inhibits bladder cancer progression by targeting lactate dehydrogenase A. Oncotarget 8, 67663–67669 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gao, C., Wei, J., Tang, T. & Huang, Z. Role of microRNA‑33a in malignant cells (Review). Oncol. Lett. 20, 2537–2556 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dávalos, A., Goedeke, L., Smibert, P., Ramírez, C. M., Warrier, N. P., Andreo, U. et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl. Acad. Sci. USA 108, 9232–9237 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wei, S., Fan, Q., Yang, L., Zhang, X., Ma, Y., Zong, Z. et al. Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling. Oncol. Rep. 38, 1902–1908 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, X., Liang, Y., Song, R., Yang, G., Han, J., Lan, Y. et al. Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation. Mol. Cancer 17, 90 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gaude, E. & Frezza, C. Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat. Commun. 7, 13041 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ito, S., Fukusato, T., Nemoto, T., Sekihara, H., Seyama, Y. & Kubota, S. Coexpression of glucose transporter 1 and matrix metalloproteinase-2 in human cancers. J. Natl. Cancer Inst. 94, 1080–1091 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Anderson, M., Marayati, R., Moffitt, R. & Yeh, J. J. Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. Oncotarget 8, 56081–56094 (2017).

    Article  PubMed  Google Scholar 

  57. Chen, G., Zhang, Y., Liang, J., Li, W., Zhu, Y., Zhang, M. et al. Deregulation of Hexokinase II Is Associated with Glycolysis, Autophagy, and the Epithelial-Mesenchymal Transition in Tongue Squamous Cell Carcinoma under Hypoxia. BioMed Res. Int. 2018, 1–15 (2018).

    Google Scholar 

  58. Ahmad, A., Aboukameel, A., Kong, D., Wang, Z., Sethi, S., Chen, W. et al. Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res. 71, 3400–3409 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu, K., Tang, Z., Huang, A., Chen, P., Liu, P., Yang, J. et al. Glyceraldehyde-3-phosphate dehydrogenase promotes cancer growth and metastasis through upregulation of SNAIL expression. Int. J. Oncol. 50, 252–262 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Hamabe, A., Konno, M., Tanuma, N., Shima, H., Tsunekuni, K., Kawamoto, K. et al. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Proc. Natl. Acad. Sci. USA 111, 15526–15531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tanaka, F., Yoshimoto, S., Okamura, K., Ikebe, T. & Hashimoto, S. Nuclear PKM2 promotes the progression of oral squamous cell carcinoma by inducing EMT and post-translationally repressing TGIF2. Oncotarget 9, 33745–33761 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wu, N., He, C., Zhu, B., Jiang, J., Chen, Y. & Ma, T. 3-Phosphoinositide Dependent Protein Kinase-1 (PDK-1) Promotes Migration and Invasion in Gastric Cancer Cells Through Activating the NF-κB Pathway. Oncol. Res. 25, 1153–1159 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhang, M., Cong, Q., Zhang, X.-Y., Zhang, M.-X., Lu, Y.-Y. & Xu, C.-J. Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation. J. Cell. Physiol. 234, 6361–6370 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Sun, Y., Daemen, A., Hatzivassiliou, G., Arnott, D., Wilson, C., Zhuang, G. et al. Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells. Cancer Metab 2, 20 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Lin, Q., He, Y., Wang, X., Zhang, Y., Hu, M., Guo, W. et al. Targeting pyruvate carboxylase by a small molecule suppresses breast cancer progression. Adv. Sci. 7, 1903483 (2020).

    Article  CAS  Google Scholar 

  66. Zhang, Y., Lin, S., Chen, Y., Yang, F. & Liu, S. LDH-A promotes epithelial–mesenchymal transition by upregulating ZEB2 in intestinal-type gastric cancer. Onco. Targets Ther. 11, 2363–2373 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, X., Zhang, Z., Zhang, Y., Cao, Y., Wei, H. Wu, Z. Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation. J. Exp. Clin. Cancer Res. 37, 39 (2018).

  68. Oginuma, M., Harima, Y., Tarazona, O. A., Diaz-Cuadros, M., Michaut, A., Ishitani, T. et al. Intracellular pH controls WNT downstream of glycolysis in amniote embryos. Nature 584, 98–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nath, A. & Chan, C. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Sci. Rep. 6, 18669 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nath, A., Li, I., Roberts, L. R. & Chan, C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci. Rep. 5, 14752 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Patel, A., Sabbineni, H., Clarke, A. & Somanath, P. R. Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis. Life Sci. 157, 52–61 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 749 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Lee, S. Y., Jeon, H. M., Ju, M. K., Jeong, E. K., Kim, C. H., Park, H. G. et al. Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch. Oncotarget 7, 7925–7939 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Kuo, T.-C., Chen, C.-K., Hua, K.-T., Yu, P., Lee, W.-J., Chen, M.-W. et al. Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells. Cancer Letters 383, 282–294 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Ramirez-Peña, E., Arnold, J., Shivakumar, V., Joseph, R., Vijay, G. V., den Hollander, P. et al. The epithelial to mesenchymal transition promotes glutamine independence by suppressing GLS2 expression. Cancers 11, 1610 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  76. Liu, G., Zhu, J., Yu, M., Cai, C., Zhou, Y., Yu, M. et al. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J. Transl. Med. 13, 144 (2015).

  77. Wang, Y., Fu, L., Cui, M., Wang, Y., Xu, Y., Li, M. et al. Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1. Cancer Lett. 393, 8–15 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Tian, Q., Yuan, P., Quan, C., Li, M., Xiao, J., Zhang, L. et al. Phosphorylation of BCKDK of BCAA catabolism at Y246 by Src promotes metastasis of colorectal cancer. Oncogene 39, 3980–3996 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bates, S. E. Epigenetic therapies for cancer. N. Engl. J. Med. 383, 650–663 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16, 694–707 (2016).

    Article  CAS  PubMed  Google Scholar 

  81. Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S. & Moro, L. Mitochondrial dysfunction: a novel potential driver of epithelial-to-mesenchymal transition in cancer. Front. Oncol. 7, 295 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Guha, M., Srinivasan, S., Ruthel, G., Kashina, A. K., Carstens, R. P., Mendoza, A. et al. Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells. Oncogene 33, 5238–5250 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Wu, W.-S. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 25, 695–705 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Lu, M., Zhu, W.-W., Wang, X., Tang, J.-J., Zhang, K.-L., Yu, G.-Y. et al. ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition. Cell Metabolism 29, 886–900.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Qin, Z.-Y., Wang, T., Su, S., Shen, L.-T., Zhu, G.-X., Liu, Q. et al. BRD4 promotes gastric cancer progression and metastasis through acetylation-dependent stabilization of Snail. Cancer Res. 79, 4869–4881 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Islam, M. S., Leissing, T. M., Chowdhury, R., Hopkinson, R. J. & Schofield, C. J. 2-Oxoglutarate-dependent oxygenases. Annu. Rev. Biochem. 87, 585–620 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Atlante, S., Visintin, A., Marini, E., Savoia, M., Dianzani, C., Giorgis, M. et al. α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis. Cell Death Dis. 9, 756 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang, M. & Pollard, P. J. Succinate: a new epigenetic hacker. Cancer cell 23, 709–711 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Fuhler, G. M., Eppinga, H. & Peppelenbosch, M. P. Fumarates and cancer. Trends Mol. Med. 23, 3–5 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J. et al. Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci. Rep. 6, 36289 (2016).

  92. Letouzé, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).

    Article  PubMed  CAS  Google Scholar 

  93. Sciacovelli, M., Gonçalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S. H., Gaude, E. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shaul, Y. D., Freinkman, E., Comb, W. C., Cantor, J. R., Tam, W. L., Thiru, P. et al. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 158, 1094–1109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schwab, A., Siddiqui, A., Vazakidou, M. E., Napoli, F., Böttcher, M., Menchicchi, B. et al. Polyol pathway links glucose metabolism to the aggressiveness of cancer cells. Cancer Res. 78, 1604–1618 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Ramesh, V., Brabletz, T., Ceppi, P. & Targeting, E. M. T. Cancer with repurposed metabolic inhibitors. Trends Cancer Res. 6, 942–950 (2020).

    Article  CAS  Google Scholar 

  97. Bocci, F., Tripathi, S. C., Vilchez Mercedes, S. A., George, J. T., Casabar, J. P., Wong, P. K. et al. NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. Integr. Biol. 11, 251–263 (2019).

    Article  Google Scholar 

  98. Colacino, J. A., Azizi, E., Brooks, M. D., Harouaka, R., Fouladdel, S., McDermott, S. P. et al. Heterogeneity of human breast stem and progenitor cells as revealed by transcriptional profiling. Stem Cell Reports 10, 1596–1609 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Luo, M., Shang, L., Brooks, M. D., Jiagge, E., Zhu, Y., Buschhaus, J. M. et al. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab. 28, 69–86.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Medina, M. Á. Mathematical modeling of cancer metabolism. Crit. Rev. Oncol. Hematol. 124, 37–40 (2018).

    Article  PubMed  Google Scholar 

  101. Orth, J. D., Thiele, I. & Palsson, B. Ø. What is flux balance analysis? Nat. Biotechnol. 28, 245–248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jia, D., Paudel, B. B., Hayford, C. E., Hardeman, K. N., Levine, H., Onuchic, J. N. et al. Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype. Front. Oncol. 10, 1426 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kang, X., Wang, J. & Li, C. Exposing the underlying relationship of cancer metastasis to metabolism and epithelial-mesenchymal transitions. iScience 21, 754–772 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Yu, L., Lu, M., Jia, D., Ma, J., Ben-Jacob, E., Levine, H. et al. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res. 77, 1564–1574 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA

    Dongya Jia, Shubham Tripathi, Madeline Galbraith, Youyuan Deng & José N. Onuchic

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Jun Hyoung Park, Kwang Hwa Jung, Sukjin Yang & Benny Abraham Kaipparettu

  3. Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India

    Harsimran Kaur & Mohit Kumar Jolly

  4. PhD Program in Systems, Synthetic, and Physical Biology, Rice University, Houston, TX, USA

    Shubham Tripathi

  5. Center for Theoretical Biological Physics and Department of Physics, Northeastern University, Boston, MA, USA

    Shubham Tripathi & Herbert Levine

  6. Department of Physics and Astronomy, Rice University, Houston, TX, USA

    Madeline Galbraith & José N. Onuchic

  7. Applied Physics Graduate Program, Rice University, Houston, TX, USA

    Youyuan Deng

  8. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Benny Abraham Kaipparettu

  9. Department of Chemistry, Rice University, Houston, TX, USA

    José N. Onuchic

  10. Department of Biosciences, Rice University, Houston, TX, USA

    José N. Onuchic

  11. Department of Bioengineering, Northeastern University, Boston, MA, USA

    Herbert Levine

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  1. Dongya Jia
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Contributions

D.J., B.A.K., J.N.O. and H.L. conceptualized the review. D.J., J.H.P., H.K., K.W.J., S.Y., S.T., M.G., Y.D. and M.K.J. contributed to writing early drafts of the paper. D.J., B.A.K., J.N.O. and H.L. revised the final version of the paper.

Corresponding authors

Correspondence to Dongya Jia, Benny Abraham Kaipparettu, José N. Onuchic or Herbert Levine.

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Competing interests

The authors declare no competing interests.

Funding information

This work is supported by the National Science Foundation (NSF) Center for Theoretical Biological Physics (NSF PHY-2019745) and NSF grants nos. PHY-1605817, PHY-1522550, and CHEM-1614101. J.N.O. is a CPRIT Scholar in Cancer Research. D.J. is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT grant no. RP170593). M.G. is supported by the NSF GRFP no. 1842494. B.A.K. is supported by NIH grants nos. CA253445, CA234479, DK117001 and CA235113 and DOD grant no. W81XWH-18-1-0714. M.K.J. is supported by Ramanujan Fellowship awarded by Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India (SB/S2/RJN-049/2018).

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Jia, D., Park, J.H., Kaur, H. et al. Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer. Br J Cancer 124, 1902–1911 (2021). https://doi.org/10.1038/s41416-021-01385-y

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  • DOI: https://doi.org/10.1038/s41416-021-01385-y

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