How do prostate cancer cells become resistant to therapy?
Acquired resistance to targeted therapies in cancer is a rising unmet clinical need. In prostate cancer (PCa), the success of next-generation androgen receptor (AR) pathway inhibitors has been hampered by the development of drug resistance. This acquired resistance involves, in many cases, the reactivation of the AR axis through several different mechanisms. However, an alternative mechanism of resistance is driven by the reprogramming of prostate cancer cells to undergo lineage plasticity to adopt an AR-independent state and to acquire a neuroendocrine phenotype, that allow them to grow and survive and escape AR-therapy. More potent and sustained AR targeting has driven an increased incidence of neuroendocrine prostate cancer (NEPC), which is an extremely aggressive, highly proliferative and metastatic PCa variant. Therefore, understanding the molecular mechanisms that govern NEPC differentiation is a pressing unmet clinical need. We are interested in unveiling the signaling and metabolic pathways that account for these changes in cell identity during therapy resistance with the goal of identifying new targets that either restore sensitivity to current therapeutics or that exploit new previously unanticipated tumor cell vulnerabilities. Our recent studies have discovered that the downregulation of PKCl/i is a hallmark of human NEPC patients. We demonstrated that the loss of PKCl/i results in the upregulation of the serine and one-carbon pathway that leads to increased production of S-adenosine methionine, universal and obligated methyl donor for DNA and histone methylation. Our present work aims to unravel the epigenetic mechanisms linking metabolic reprogramming by PKCl/i to cell lineage alterations in PCa and possibly therapy resistance in other types of cancers. We are also investigating how the remodeling of the tumor microenvironment, particularly the stromal fibroblasts, facilitates therapy resistance, and how the metabolic interplay between cancer-associated fibroblasts and the epithelial compartment of the tumor informs new therapies.
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 PKCl/i 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]
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, 818-829. PMC5718961
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]
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. Mol. Cell. 51, 283-296. PMC3971544
Kim, J.Y, Valencia, T., Abu-Baker, S., Linares, J.F., Lee, S.J., Yajima, T., Chen, J., Eroshkin, A., Castilla, E.A., Brill, L.M., Medvedovic, M., Leitges, M., Moscat, J., Diaz-Meco, M.T. (2013) c-Myc Phosphorylation by PKCz Represses Prostate Tumorigenesis. Proc. Natl. Acad. Sci. USA 110(16):6418-23 [Direct Submission]. PMC3631641
Duran, A., Amanchy, R., Linares, J.F., Joshi, J., Abu-Baker, S., Porollo, A., Hansen, M., Moscat, J., Diaz-Meco, M.T. (2011) p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell 44, 134-146 [Highlighted in a Preview in the same issue]. PMC3190169