The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer
Authors: Young A Yoo, Rajita Vatapalli, Barbara Lysy, Hanlin Mok, Mohamed M Desouki, Sarki A Abdulkadir
Journal: JNCI Journal of the National Cancer Institute (2018)

Background: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined.We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of-origin.Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo.Methods: We employed lineage retracing in Bmi1-Cre ER ; R26R-confetti; Pten f/f transgenic mice to mark and follow the fate of emerging recurrent tumor clones after castration.A tissue recombination strategy was used to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts.We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence.Results: Transgenic prostate tumors (n ¼ 17) regressed upon castration but uniformly recurred within 3 months.Residual regressed tumor lesions exhibited a transient luminal-to-basal phenotypic switch and marked cellular heterogeneity.Additionally, in these lesions, a subpopulation of Bmi1-expressing castration-resistant tumor cells overexpressed the stem cell reprogramming factor Sox2 (mean [SD] ¼ 41.1 [3.8]%, n ¼ 10, P < .001).Bmi1þSox2þ cells were quiescent (BrdUþBmi1þSox2þ at 3.4 [1.5]% vs BrdUþBmi1þSox2-at 18.8 [3.4]%, n ¼ 10, P ¼ .009),consistent with a cancer stem cell phenotype.By lineage retracing, we established that recurrence emerges from the Bmi1þ tumor cells in regressed tumors.Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 reduced Bmi1þSox2þ cells (6.1 [1.4]% PTC-209 vs 38.8 [2.3]% vehicle, n ¼ 10, P < .001)and potently suppressed recurrence (retraced clone size ¼ 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n ¼ 12, P ¼ .04).Conclusions: These results illustrate the utility of lineage retracing to define the cellular origins of recurrent prostate cancer and identify Bmi1þSox2þ cells as a source of recurrence that could be targeted therapeutically.Most advanced prostate cancers are initially dependent on androgen signaling for survival at the time of initial diagnosis (1), making androgen deprivation therapy (ADT) the standard treatment option for these patients (2).However, failure of ADT is common, resulting in tumor recurrence as castration resistant prostate cancer (CRPC) (3,4).An emerging model of resistance to ADT in prostate cancer, particularly to the more potent newer antiandrogen drugs such as enzalutamide and abiraterone, involves lineage plasticity or transdifferentiation (5-8).Epigenetic regulators and stem cell reprogramming factors including Sox2 and Ezh2 appear to play important roles in this process (5,6).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 CRPC.In prostate cancer, the polycomb repressor complex 1 protein Bmi1 has been implicated in promoting tumor progression, stemness, and chemoresistance (9-13).We recently identified a population of luminal progenitors termed castration-resistant