Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming
Rajeev Mishra, … , Edwin M. Posadas, Neil A. Bhowmick
Rajeev Mishra, … , Edwin M. Posadas, Neil A. Bhowmick
Published July 26, 2018
Citation Information: J Clin Invest. 2018;128(10):4472-4484. https://doi.org/10.1172/JCI99397.
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Research Article Cell biology Metabolism

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

Abstract

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.

Authors

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

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Figure 7

Sensitivity to ADT correlating with blood glutamine levels is in support of a model of epigenetic Ras activation in prostatic fibroblasts and glutamine-mediated paracrine activity on PCa epithelia.

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Sensitivity to ADT correlating with blood glutamine levels is in support...
(A) Waterfall plot of plasma glutamine concentration in PCa patients on ADT correlated to therapeutic response (n = 28; see Table 1). Based on serum PSA detection, patients were determined to be responsive (green bars) and nonresponsive (red bars) to ADT. The threshold of 2 mM glutamine was chosen as a determinant of ADT responsiveness. Fisher’s exact test was used to determine odds ratio. (B) While RASAL3 promoter hypermethylation and gene silencing are observed in CAF compared with NAF, androgen-targeted therapy furthers this epigenetic Ras activation process that induces macropinocytosis in stromal fibroblasts for the uptake of albumin. Albumin is degraded by the lysosomes to generate glutamine and shuttled into epithelia through the glutamine transporter SLC1A5. Glutamine is converted to glutamate and α-ketoglutarate (αKG) in entering the TCA cycle in support of PCa epithelial proliferation. Glutamine also contributes to mTOR activation, leading to neuroendocrine differentiation (NED).