7.344 | Fall 2018 | Undergraduate

Cellular Metabolism and Cancer: Nature or Nurture?



Introduction to the Course

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An Introduction to Cancer Metabolism: The Warburg Effect

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Cori, C.F., and Cori, G.T. (1925). “The carbohydrate metabolism of tumors. II. Changes in the sugar, lactic acid, and co-combing power of blood passing through a tumor (PDF).” Journal of Biological Chemistry 65, 397–405.

Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., and Cantley, L. C. (2008). “The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.” Nature 452, 230–233.


Role of Mitochondrial Function in Tumor Cell Growth

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Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R., and Chandel, N. S. (2010). “Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity.” Proc Natl Acad Sci USA 107, 8788–8793.

Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., and Sabatini, D. M. (2015). “An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis.” Cell 162, 540–551.


Amino Acid Metabolism

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Hosios, A. M., Hecht, V. C., Danai, L. V., Johnson, M. O., Rathmell, J. C., Steinhauser, M. L., et al. (2016). “Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells.” Developmental Cell, 36, 540–549.

Labuschagne, C. F., van den Broek, N. J. F., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. K. (2014). “Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells.” Cell Reports, 7, 1248–1258.


Nucleotide and Lipid Metabolism

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Lunt, S. Y., Muralidhar, V., Hosios, A. M., Israelsen, W. J., Gui, D. Y., Newhouse, L., Ogrodzinski, M., Hecht, V., Xu, K., Acevedo, P. N., Hollern, D. P., Bellinger, G., Dayton, T. L., Christen, S., Elia, I., Dinh, A. T., Stephanopoulos, G., Manalis, S. R., Yaffe, M. B., Andrechek, E. R., Fendt, S. M., and Vander Heiden, M. G. (2015). “Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.” Molecular Cell 57, 95–107.

Svensson, R. U., Parker, S. J., Eichner, L. J., Kolar, M. J., Wallace, M., Brun, S. N., Lombardo, P. S., Van Nostrand, J. L., Hutchins, A., Vera, L., Gerken, L., Greenwood, J., Bhat, S., Harriman, G., Westlin, W. F., Harwood, H. J., Saghatelian, A., Kapeller, R., Metallo, C. M., and Shaw, R. J. (2016). “Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.” Nature Medicine 22, 1108–1119.


Mutations in Isocitrate Dehydrogenase and the Discovery of a Neomorphic Activity

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Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., Ding, J., Lei, Q., Guan, K. L., and Xiong, Y. (2009). “Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.” Science 324, 261–265.

Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., Rabinowitz, J. D., Carroll, M., Su, S. M., Sharp, K. A., Levine, R. L., and Thompson, C. B. (2010). “The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.” Cancer Cell 17, 225–234.


2-hydroxyglutarate: The First Oncometabolite?

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Chowdhury, R., Yeoh, K. K., Tian, Y. M., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., McDonough, M. A., King, O. N., Clifton, I. J., Klose, R. J., Claridge, T. D. W., Ratcliffe, P. J., Schofield, C. J., and Kawamura, A. (2011). “The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.” Embo Reports 12, 463–469.

Intlekofer, A. M., Shih, A. H., Wang, B., Nazir, A., Rustenburg, A. S., Albanese, S. K., Patel, M., Famulare, C., Correa, F.M., Takemoto, N., Durani, V., Liu, H., Taylor, J., Farnoud, N., Papaemmanuil, E., Cross, J.R., Tallman, M.S., Arcila, M.E., Roshal, M., Petsko, G.A., Wu, B., Choe, S., Konteatis, Z.D., Biller, S.A., Chodera, J.D., Thompson, C.B., Levine, R.L., Stein, E.M. (2018). “Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations.” Nature 559, 125–129.


Field Trip—Visit to Agios

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Oncogenes and Metabolism: How Genetic Changes Alter Cancer Metabolism

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Son, J., Lyssiotis, C.A., Ying, H.Q., Wang, X.X., Hua, S.J., Ligorio, M., Perera, R.M., Ferrone, C.R., Mullarky, E., Shyh-Chang, N., Kang, Y., Fleming, J.B., Bardeesy, N., Asara, J.M., Haigis, M.C., DePinho, R.A., Cantley, L.C., Kimmelman, A.C. (2013). “Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.” Nature 496, 101–105.

Yuneva, M. O., Fan, T. W. M., Allen, T. D., Higashi, R. M., Ferraris, D. V., Tsukamoto, T., Mates, J. M., Alonso, F. J., Wang, C. M., Seo, Y., Chen, X., and Bishop, J. M. (2012). “The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type.” Cell Metabolism 15, 157–170.


Context Matters! How Tissue Environment Alters Cancer Cell Metabolism

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Davidson, S. M., Papagiannakopoulos, T., Olenchock, B. A., Heyman, J. E., Keibler, M. A., Luengo, A., Bauer, M. R., Jha, A. K., O’Brien, J. P., Pierce, K. A., Gui, D. Y., Sullivan, L. B., Wasylenko, T. M., Subbaraj, L., Chin, C. R., Stephanopolous, G., Mott, B. T., Jacks, T., Clish, C. B., and Vander Heiden, M. G. (2016). “Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer.” Cell Metabolism 23, 517–528.

Cantor, J. R., Abu-Remaileh, M., Kanarek, N., Freinkman, E., Gao, X., Louissaint, A., Lewis, C. A., and Sabatini, D. M. (2017). “Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase.” Cell 169, 258–272.e17.


Metabolic Interactions of Stroma Cells and Cancer

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Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Hwang, R.F., Witkiewicz, A.K., Ying H, Asara, J.M., Evans, R.M., Cantley, L.C., Lyssiotis, C.A., Kimmelman, A.C. (2016). “Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.” Nature 536, 479–483.

Linares, J. F., Cordes, T., Duran, A., Reina-Campos, M., Valencia, T., Ahn, C. S., Castilla, E.A., Moscat, J., Metallo, C.M., Diaz-Meco, M.T. (2017). “ATF4-induced metabolic reprograming is a synthetic vulnerability of the p62-deficient tumor stroma.” Cell Metabolism 26, 817–829.e6.


Impact of Diet on Tumor Metabolism and Progression

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Maddocks, O. D. K., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., van den Broek, N. J. F., Mackay, G. M., Labuschagne, C. F., Gay, D., Kruiswijk, F., Blagih, J., Vincent, D. F., Campbell, K. J., Ceteci, F., Sansom, O. J., Blyth, K., and Vousden, K. H. (2017). “Modulating the therapeutic response of tumours to dietary serine and glycine starvation.” Nature 544, 372–376.

Hopkins, B. D., Pauli, C., Du, X., Wang, D. G., Li, X., Wu, D., Amadiume, S. C., Goncalves, M. D., Hodakoski, C., Lundquist, M. R., Bareja, R., Ma, Y., Harris, E. M., Sboner, A., Beltran, H., Rubin, M. A., Mukherjee, S., and Cantley, L. C. (2018). “Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.” Nature, 560, 499–503.


Oral Presentations and Final Discussion

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Course Info

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Fall 2018
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