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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

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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 3

Ras activation in CAF drives glutamine metabolism in epithelia.

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Ras activation in CAF drives glutamine metabolism in epithelia.
(A) Rela...
(A) Relative mRNA expression levels of CAF-marker genes in WT and RasV12 mouse fibroblasts determined by quantitative RT-PCR and analyzed using 2-way ANOVA (n = 3). (B) EpCAM-positive cancer epithelium was quantitated by FACS of 3D cocultures of human epithelial (CWR22Rv1) cells and WT or RasV12 mouse fibroblasts. Statistical analysis was performed using 2-tailed Student’s t test (n = 3). (C) ATP was measured in CWR22Rv1 after incubation with CM human NAF or CAF or mouse WT or RasV12 fibroblast or oligomycin in glutamine-free media (n = 3). Statistical analysis was performed using 1-way ANOVA with multiple comparisons. (D) Diagram represents the TCA cycle in CWR22Rv1 cells treated with NAF or CAF CM for 72 hours prior to metabolome analysis (n = 3). (E) Metabolome analysis further indicated differential flux to aspartate, oxidized GSH, and GSH reduced in CWR22Rv1 cells incubated with NAF or CAF CM. (F) Glutamine concentrations (Gln conc.) were measured in the CM from indicated mouse fibroblasts cultured for 72 hours. cond, conditioned. (D–F) Statistical analysis was performed using 2-tailed Student’s t test (n = 3). (G) CWR22Rv1 proliferation was measured by cell counting following incubation with NAF and CAF CM for 72 hours in glutamine-free media. NAF CM was supplemented with 0.4 mM glutamine to mimic the glutamine levels expressed by CAF (see Supplemental Figure 4B). Statistical analysis was performed using 1-way ANOVA with multiple comparisons (n = 3). (H) Proton magnetic resonance spectroscopy data were acquired from orthotopically xenografted mice before and after EIPA administration. Spectra of the unfiltered data are superimposed using simulated echo acquisition (n = 3–4 per group). Glu, gllutamate; ppm, parts per million. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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