Transient Sox9 Expression Facilitates Progression to Castrate Resistant Prostate Cancer

Purpose: Metastatic prostate cancer (PCa) patients are increasingly presenting with treatment-resistant, androgen receptor-Negative/Low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here we explore the role of the developmental transcription factor Sox9 in the process of PCa therapy response and tumor progression. Experimental Design: Unique PCa cell models that capture AR-/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human PCa xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. Results: PCa stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of PCa cells. Sox9 was transiently upregulated in castration-induced progression of PCa xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT) treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in PCa cells. Conclusions: Developmentally reprogrammed PCa cell models recapitulate features of clinically-advanced prostate tumors including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies PCa cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.