Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4472-4484
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number10
DOIs
StatePublished - Oct 1 2018

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Epigenomics
Glutamine
Prostatic Neoplasms
Androgens
Heterografts
Therapeutics
Castration
Growth and Development
Prostate
Adenocarcinoma
Epithelium
Fibroblasts
Odds Ratio
Cancer-Associated Fibroblasts
Neoplasms

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Mishra, R., Haldar, S., Placencio, V., Madhav, A., Rohena-Rivera, K., Agarwal, P., ... Bhowmick, N. A. (2018). Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. Journal of Clinical Investigation, 128(10), 4472-4484. https://doi.org/10.1172/JCI99397
Mishra, Rajeev ; Haldar, Subhash ; Placencio, Veronica ; Madhav, Anisha ; Rohena-Rivera, Krizia ; Agarwal, Priyanka ; Duong, Frank ; Angara, Bryan ; Tripathi, Manisha ; Liu, Zhenqiu ; Gottlieb, Roberta A. ; Wagner, Shawn ; Posadas, Edwin M. ; Bhowmick, Neil A. / Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 10. pp. 4472-4484.
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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 2018, 'Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming', Journal of Clinical Investigation, vol. 128, no. 10, pp. 4472-4484. https://doi.org/10.1172/JCI99397

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. / Mishra, Rajeev; Haldar, Subhash; Placencio, Veronica; Madhav, Anisha; Rohena-Rivera, Krizia; Agarwal, Priyanka; Duong, Frank; Angara, Bryan; Tripathi, Manisha; Liu, Zhenqiu; Gottlieb, Roberta A.; Wagner, Shawn; Posadas, Edwin M.; Bhowmick, Neil A.

In: Journal of Clinical Investigation, Vol. 128, No. 10, 01.10.2018, p. 4472-4484.

Research output: Contribution to journalArticle

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AU - Mishra, Rajeev

AU - Haldar, Subhash

AU - Placencio, Veronica

AU - Madhav, Anisha

AU - Rohena-Rivera, Krizia

AU - Agarwal, Priyanka

AU - Duong, Frank

AU - Angara, Bryan

AU - Tripathi, Manisha

AU - Liu, Zhenqiu

AU - Gottlieb, Roberta A.

AU - Wagner, Shawn

AU - Posadas, Edwin M.

AU - Bhowmick, Neil A.

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Y1 - 2018/10/1

N2 - 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.

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Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. Journal of Clinical Investigation. 2018 Oct 1;128(10):4472-4484. https://doi.org/10.1172/JCI99397