Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming.

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018 Jul 26;: Authors: Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, Duong F, Angara B, Tripathi M, Liu Z, Gottlieb RA, Wagner S, Posadas EM, Bhowmick NA Abstract Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelia and its microenvironment. Here, we found epigenetic changes in cancer-associated prostatic fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified that a Ras inhibitor, RASAL3, is epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In a orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castrate resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with th...
Source: Clinical Prostate Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research