CXCR4-LASP1-G9a-SNAIL Axis Drives NEPC Transdifferentiation via Induction of EMT and Downregulation of REST [16D CRPC xenograft]

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that can develop from prostate cancer following aggressive hormonal therapy. Unfortunately, there are few treatment options available and new therapeutic targets and more effective treatments are urgently needed to improve management of the disease. There is now little doubt that the majority of NEPC is derived from prostatic adenocarcinoma cells via “NE transdifferentiation” that is driven at least in part by AR-axis interference and lineage plasticity. We have developed a first-in-field patient-derived xenograft model of a prostatic adenocarcinoma (LTL331) that undergoes a complete transdifferentiation to NEPC (LTL331R) upon host castration. Using this unique, high-fidelity, patient-derived prostate cancer xenograft models and powerful genomic and transcriptomic analyses, we have obtained evidence that therapy induced development of NEPC may result from epigenetic alterations which drives lineage plasticity of dormancy-capable cancer cells and functional evaluation of key regulators. These findings may lead to more suitable targets and better therapeutic strategies for prevention and treatment of NEPC.