Prostate cancer is an androgen-dependent disease; therefore, current approaches for treatment aim to disrupt androgen signaling. Unfortunately, this approach is rarely curative due to the selection of resistant clones and adaptation of stromal and endothelial cells to support tumor growth. In this episode, Neil Bhowmick and colleagues evaluated epigenetic alterations in prostate cancer-associated fibroblasts (CAFs) and determined that the Ras inhibitor RASAL3 is silenced in these cells, thereby driving macropinocytosis-mediated glutamine synthesis due to increased oncogenic Ras activity. The increase in stromal glutamine associated with neuroendocrine differentiation, and in prostate cancer patients, blood glutamine levels were elevated in patients that were resistant to androgen deprivation compared to those that were responsive. Together, these results suggest that strategies to prevent glutamine uptake be considered in conjunction with androgen deprivation.
Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated 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 a Ras inhibitor, RASAL3, as 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 an 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 castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.
Rajeev Mishra, Subhash Haldar, Veronica Placencio, Anisha Madhav, Krizia Rohena-Rivera, Priyanka Agarwal, Frank Duong, Bryan Angara, Manisha Tripathi, Zhenqiu Liu, Roberta A. Gottlieb, Shawn Wagner, Edwin M. Posadas, Neil A. Bhowmick