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Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

ABSTRACT: Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

SUBMITTER: Giafaglione JM

PROVIDER: S-EPMC10709144 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Giafaglione Jenna M JM Crowell Preston D PD Delcourt Amelie M L AML Hashimoto Takao T Ha Sung Min SM Atmakuri Aishwarya A Nunley Nicholas M NM Dang Rachel M A RMA Tian Mao M Diaz Johnny A JA Tika Elisavet E Payne Marie C MC Burkhart Deborah L DL Li Dapei D Navone Nora M NM Corey Eva E Nelson Peter S PS Lin Neil Y C NYC Blanpain Cedric C Ellis Leigh L Boutros Paul C PC Goldstein Andrew S AS

Nature cell biology 20231204 12

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit ...[more]

PMID: 38049604

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Project description:Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance.Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray.Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth.Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer. Clin Cancer Res; 24(18); 4551-65. ©2018 AACR.

Dataset Information

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Publications

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

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