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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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.
AbstractList	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. 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.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.
Audience	Academic
Author	Posadas, Edwin M. Rohena-Rivera, Krizia Tripathi, Manisha Placencio, Veronica Haldar, Subhash Duong, Frank Angara, Bryan Wagner, Shawn Mishra, Rajeev Agarwal, Priyanka Liu, Zhenqiu Bhowmick, Neil A. Madhav, Anisha Gottlieb, Roberta A.
AuthorAffiliation	3 Department of Research, Greater Los Angeles Veterans Administration, Los Angeles, California, USA 1 Department of Medicine, and 2 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
AuthorAffiliation_xml	– name: 1 Department of Medicine, and – name: 2 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA – name: 3 Department of Research, Greater Los Angeles Veterans Administration, Los Angeles, California, USA
Author_xml	– sequence: 1 givenname: Rajeev surname: Mishra fullname: Mishra, Rajeev – sequence: 2 givenname: Subhash orcidid: 0000-0002-1230-1770 surname: Haldar fullname: Haldar, Subhash – sequence: 3 givenname: Veronica surname: Placencio fullname: Placencio, Veronica – sequence: 4 givenname: Anisha surname: Madhav fullname: Madhav, Anisha – sequence: 5 givenname: Krizia surname: Rohena-Rivera fullname: Rohena-Rivera, Krizia – sequence: 6 givenname: Priyanka surname: Agarwal fullname: Agarwal, Priyanka – sequence: 7 givenname: Frank surname: Duong fullname: Duong, Frank – sequence: 8 givenname: Bryan surname: Angara fullname: Angara, Bryan – sequence: 9 givenname: Manisha surname: Tripathi fullname: Tripathi, Manisha – sequence: 10 givenname: Zhenqiu orcidid: 0000-0003-1535-4322 surname: Liu fullname: Liu, Zhenqiu – sequence: 11 givenname: Roberta A. orcidid: 0000-0002-1432-006X surname: Gottlieb fullname: Gottlieb, Roberta A. – sequence: 12 givenname: Shawn surname: Wagner fullname: Wagner, Shawn – sequence: 13 givenname: Edwin M. surname: Posadas fullname: Posadas, Edwin M. – sequence: 14 givenname: Neil A. orcidid: 0000-0001-8747-5989 surname: Bhowmick fullname: Bhowmick, Neil A.
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30047926$$D View this record in MEDLINE/PubMed
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Snippet	Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic...
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SubjectTerms	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
Title	Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming
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