The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer.

ABSTRACT: 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-CreER; R26R-confetti; Ptenf/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?=?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]?=?41.1 [3.8]%, n?=?10, P?

SUBMITTER: Yoo YA 

PROVIDER: S-EPMC6410937 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature