A significant subset of patients with the treatment-resistant disease develops AR-negative prostate tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC) 1, 2, 3). Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.ĭespite advances in the development of highly effective androgen receptor (AR)-targeted therapies for the treatment of men with advanced prostate cancer acquired resistance ultimately ensues. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. 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. 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. The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. 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)). Nature Communications volume 12, Article number: 3372 ( 2021)ĭespite 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.
Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer
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