Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

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 pros...

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Veröffentlicht in:The Journal of clinical investigation Jg. 128; H. 10; S. 4472 - 4484
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.10.2018
Schlagworte:
Animals
Care and treatment
Diagnosis
Fibroblasts - metabolism
Fibroblasts - pathology
Gene mutation
Gene Silencing
Genetic aspects
Glutamine - genetics
Glutamine - metabolism
Health aspects
Hormone therapy
Humans
Male
Methods
Mice
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Neuroendocrine Tumors - genetics
Neuroendocrine Tumors - metabolism
Neuroendocrine Tumors - pathology
Patient outcomes
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
ras GTPase-Activating Proteins - genetics
ras GTPase-Activating Proteins - metabolism
Epigenetics
Metabolism
Molecular biology
Cancer
Cell Biology
ISSN:0021-9738, 1558-8238, 1558-8238
Online-Zugang:Volltext
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI99397