The androgen receptor (AR) is the key oncogenic driver of prostate cancer and despite implementation of novel AR targeting therapies, patient outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen regulated cellular processes, in order to more effectively target the AR-dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, however the relationship between AR and the lipidome remain undefined. Using mass spectrometrybased lipidomics, this study revealed increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgenregulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL Fatty Acid Elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts and clinical tumors. Assessment of mRNA and protein in large-scale datasets revealed ELOVL5 as the predominant ELOVL expressed in both primary and metastatic prostate cancer, and upregulated compared to non-malignant prostate. ELOVL5 depletion by siRNA markedly altered mitochondrial function to induce oxidative stress, resulting in significant inhibition of prostate cancer cell viability, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell viability caused by ELOVL5 knockdown. We have identified lipid elongation as a pro-survival metabolic pathway in prostate cancer that is androgenregulated, critical for metastasis and targetable via ELOVL5.
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.
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