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-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 CR...

CUL4B regulates cancer stem‐like traits of prostate cancer cells by targeting BMI1 via miR200b/c

“…PCa-stem-like cells have been implicated as tumor-initiating/maintaining cells in PCa. 35 Representative molecular markers of PCa-stem-like cells include integrin α2β1 hi , 36 Sca-1 + , 37 and ABCG2/BCRP1. 38 However, there are still many gaps to be filled in terms of how prostate cancer stem cells (PCSCs) promotes malignant progression of PCa.…”

LIN28B promotes the development of neuroendocrine prostate cancer

“…(e.g., CD44, CD133, and BMI1), reduced expression of luminal epithelial biomarkers (e.g., AR and PSA), or an altered expression of EMT-related genes (e.g., E-CAD and SNAI2), all of which are associated with castration resistance and metastasis (49)(50)(51)(52). It is worth noting that the LIN28A isoform was reported to be overexpressed in CRPC-AdPC, where it stimulates AdPC cell proliferation, anchorage-independent colony formation, and tumorigenesis (53).…”

Clonal Genetic Tracing using the Confetti Mouse to Study Mineralized Tissues

“…Due to the flexibility of the Confetti model, it has been applied to study the development and maintenance of many different tissues in health and disease 2,6,7,8,9,10,11 . One common way to use the model is to label a certain population of cells and determine which tissues they (and/or their progeny) have contributed to.…”

“…One of the advantages of the Confetti mouse is that it can be combined with a large number of genetically mutant strains that are available so that the impact of specific genes on clonal dynamics can be studied 10,11,12,13,14,19,20 , albeit with some limitations. For example, recombination of the Confetti alleles and the gene of interest cannot be separated when using Cre loxP-based mutants combined with clonal lineage tracing.…”

“…For example, recombination of the Confetti alleles and the gene of interest cannot be separated when using Cre loxP-based mutants combined with clonal lineage tracing. Nevertheless, such coinciding recombination events can be effective 10,14,20 . For example, this possibility was used to explore the increased cell number in the resting zone of mice following postnatal chondrocyte-specific ablation of TSC1 in the growth plate 21 and revealed the clonal relationship between these cells over time…”