Introduction: Recurrence is associated with mortality in prostate cancer, but the cellular origins and molecular mechanisms that drive this process have not been well-defined. An emerging model of resistance to androgen deprivation therapy (ADT) in prostate cancer, particularly to the more potent newer drugs, involves lineage plasticity or transdifferentiation. Epigenetic regulators and stem cell reprogramming factors including Sox2 and Ezh2 appear to play important roles in this process. However, there has been a paucity of studies that attempt to specifically follow the fate of malignant prostate cells in regressed tumors following castration in order to understand the cellular processes associated with the emergence of castration-resistant prostate cancer (CRPC). We recently identified a population of luminal progenitors termed castration-resistant Bmi1-expressing cells (CARBs) in the mouse prostate that serve as a prostate cancer cell of origin. Here, we hypothesized that analogous castration-resistant Bmi1-expressing tumor cells (tumor CARBs) exist in prostate cancer and could seed recurrence after ADT. Methods: We adopted lineage retracing strategies using an inducible Bmi1-CreER driver and a multicolor reporter R26R-Confetti allele, which enables lineage-marking and kinetically re-tracing of the emerging recurrent tumor clones within castrated tumors over times in vivo. A tissue recombination strategy was used to rescue transgenic Bmi1-CreER; Ptenf/f mice (BC-Pten) mouse prostates by regeneration as grafts in SCID mice. The ability of tumor CARBs to seed recurrence was determined by lineage retracing methodology of castrated mice after establishing tumor by tamoxifen treatment, which was coupled with immunohistochemistry and Western blotting. We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence. Results: Deletion of Pten in Bmi1+ luminal prostate progenitors generates a luminal prostate cancer that regresses upon castration, followed by recurrence over time. Notably, castration induced a transient luminal-to-basal phenotypic switch in regressed tumors with recurrent tumors reverting to a luminal phenotype. Analysis of regressed tumors post-castration showed cellular heterogeneity, with a population of apoptosis-resistant, proliferative, Bmi1-expressing tumor cells that also upregulate expression of the stem cell reprogramming factor Sox2. Expression of Sox2 was maintained in recurrent tumors despite loss of basal cell transdifferentiation. Lineage re-tracing with the R26R-Confetti allele established that Bmi1+ tumor cells in regressed tumors drive recurrence. Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 eliminated Bmi1+Sox2+ cells and significantly decreased recurrence. Conclusion: These results shed light on the cellular origins of recurrent prostate cancer and the roles of the epigenetic/stem cell regulators Bmi1 and Sox2 in therapeutic resistance to androgen deprivation.
Citation Format: Young A. Yoo, Rajita Vatapalli, Barbara Lysy, Hanlin Mok, Mohamed M. Desouki, Sarki A. Abdulkadir. Castration-resistant Bmi1+Sox2+ cells drive recurrence in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-046.