The Metabolism of Cancer
Tumor cells have an extremely elevated need for nutrients to sustain their high anabolic requirements necessary to maintain their enhanced proliferative rate. They are tremendously plastic and can reprogram their metabolism to more effectively use nutrients, when they are abundant, and reframe several key metabolic pathways to resist nutrient deprivation when they become aggressive and in poorly vascularized microenvironments. The study of these mechanisms opened the possibility of identifying metabolic dependencies and addictions in each type of cancer cell, which in fact become vulnerabilities that can be targeted therapeutically. Our laboratories actively explore these pathways and have very significantly contributed to the field by identifying several key mechanisms in the study of tumor metabolism. These included the serine biosynthetic and one-carbon pathways that are a central node in the control of cell energetics, oxidative detoxification, and epigenetic control through the generation of methyl donor groups for DNA and histone methylation.
Although part of the lab focuses on the metabolism of tumor cells, there is another aspect of this question that is of paramount importance and that deals with the question of total body metabolism, the metabolic syndrome, and its relationship with cancer. Our labs were the first to report the role of p62/SQSTM1 in adipocyte function. We showed that the loss of p62 in adipocytes triggered increased adiposity and obesity in mice. Interestingly, this has very important effects on cancer. Thus, we demonstrated that the loss of p62 in adipocytes results in increased osteopontin secretion, which mediates tumor fatty acid oxidation and invasion, leading to aggressive metastatic prostate cancer. Importantly, while promoting tumor malignancy, the adipocyte’s p62 deficiency promotes a general shutdown of energy-utilizing pathways in adipocytes through mTORC1 inhibition, which supports nutrient availability for cancer cells. These results exemplified the symbiotic collaboration between adipocytes and tumor cells in which p62 emerges as a central regulator.
Huang, J., Linares, J.F., Duran, A., Xia, W., Saltiel, A.R., Müller, T.D., Diaz-Meco, M.T., Moscat, J. (2021). NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ. Nat. Commun. 12, 2876. PMID: 34001883
Reina-Campos, M., Linares, J.F., Duran, A., Cordes, T., L’Hermitte, A., Badur, M.G., Bhangoo, M.S., Thorson, P.K., Richards, A., Rooslid, T., Garcia-Olmo, D.C., Nam-Cha, S.Y., Salinas-Sanchez, A.S., Eng, K., Beltran, H., Scott, D.A, Metallo, C.M., Moscat, J., Diaz-Meco, M.T. (2019). Increased Serine and One Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. Cancer Cell 35, 385-400.
Huang, J., Duran, A., Reina-Campos, M., Valencia, T., Castilla, E.A., Muller, T.D., Tschop, M.H., Moscat, J.*, Diaz-Meco, M.T.* (2018) Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor. Cancer Cell 33, 770-784. PMC5896786. [(*) Co-senior and co-corresponding authors] [Highlighted in Cancer Discovery and Nature Reviews Endocrinology]
Hernandez, E.D., Lee, S.J., Kim, J.Y., Duran, A., Linares, J.F., Yajima, T., Müller, T.D., Tschöp, M.H., Smith, S.R., Diaz-Meco, M.T., and Moscat, J. (2014) A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose-tissue inflammation in obesity. Cell Metabolism 20, 499-511. PMC4156534
Valencia, T., Kim, J.Y., Abu-Baker, S., Moscat-Pardos, J., Ahn, C.S., Reina-Campos, M., Duran, A., Castilla, E.A., Metallo, C.M., Diaz-Meco, M.T., and Moscat, J. (2014) Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26, 121-135. PMC4101061 [Highlighted in a Preview in the same issue and in Cancer Discovery and Nature Reviews in Cancer and chosen as “Best of Cancer Cell 2014” article]
Ma, L., Tao, Y., Duran, A., Llado, V., Galvez, A, Barger, J.F., Castilla, E.A., Chen, J., Yajima, T., Porollo, A., Medvedovic, M., Brill, L.M., Plas, D.R., Riedl, S.J., Leitges, M., Diaz-Meco, M.T., Richardson, A.D., and Moscat, J. (2013) Control of nutrient stress-induced metabolic reprogramming by PKCz in tumorigenesis. Cell 152, 599-611. PMC3963830 [Highlighted in Nature Genetics 45, 233 (2013)]
Linares, J.F., Duran, A., Yajima, T., Pasparakis, M., Moscat, J.*, Diaz-Meco, M.T.* (2013) K63-polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Molecular Cell 51, 283-296. [(*) Co-corresponding authors]. PMC3971544
Lee, S.J., Kim, J.Y., Nogueiras, R., Linares, J.F., Perez-Tilve, D., Jung, D.Y., Ko, H.J., Drew, A., Leitges, M., Kim, J.K., Tschöp, M.H., Diaz-Meco, M.T., Moscat, J. (2010) PKCz-driven inflammation in the non-hematopoietic compartment is critical for obesity-induced glucose intolerance. Cell Metabolism 12, 65-77. PMC2907185
Rodriguez, A., Durán, A., Selloum, M., Champy, M.F., Diez-Guerra, F.J., Flores, J.M., Serrano, M., Auwerx, J., Diaz-Meco, M.T., and Moscat, J. (2006) Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metabolism 3, 211-222. PMID: 16517408