Yoo YA, et al. - Since recurrence after androgen-deprivation therapy is linked to adverse clinical outcomes in prostate cancer and a population of castration-resistant luminal progenitor cells expressing Bmi1 has been identified in the normal mouse prostate that can serve as a cancer cell-of-origin, researchers investigated the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo. Results suggest that lineage retracing could help to define the cellular origins of recurrent prostate cancer and that Bmi1+Sox2+ cells could be targeted therapeutically as a source of recurrence.

Methods

• Using lineage retracing in Bmi1-Cre^ER; R26R-confetti; Pten^f/f transgenic mice, researchers marked and followed the fate of emerging recurrent tumor clones following castration.
• They used tissue recombination strategy to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts.
• A small molecule Bmi1 inhibitor, PTC-209, was used to directly test the role of Bmi1 in recurrence.

Results

• Researchers noted regression of transgenic prostate tumors (n = 17) upon castration, but within 3 months, these recurred uniformly.
• A transient luminal-to-basal phenotypic switch and marked cellular heterogeneity were evident in residual regressed tumor lesions.
• In these lesions, the stem cell reprogramming factor Sox2 was over-expressed in a subpopulation of Bmi1-expressing castration-resistant tumor cells (mean [SD] = 41.1 [3.8] %, n = 10, P < .001).
• Consistent with a cancer stem cell phenotype, Bmi1+Sox2+ cells were quiescent (BrdU+Bmi1+Sox2+ at 3.4 [1.5] % vs BrdU+Bmi1+Sox2- at 18.8 [3.4] %, n = 10, P=.009).
• In regressed tumors, lineage retracing established the emergence of recurrence from the Bmi1+ tumor cells.
• Treatment with the small molecule Bmi1 inhibitor PTC-209 led to reduction in Bmi1+Sox2+ cells (6.1 [1.4] % PTC-209 vs 38.8 [2.3] % vehicle, n = 10, P<.001) and potent suppression of recurrence (retraced clone size = 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n = 12, P=.04).