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Luminal-contact-inhibition of epithelial basal stem cell multipotency in prostate organogenesis and homeostasis.

ABSTRACT: Prostate epithelial basal cells are highly plastic in their luminal differentiation capability. Basal stem cells actively produce luminal cells during organogenesis, but become restricted in the adult prostate unless receiving oncogenic or inflammatory stimuli. Given that the number of luminal cells increases relative to basal cells through development and that equilibrium is reached in the adulthood, we hypothesize that a negative-feedback mechanism exists to inhibit basal-to-luminal differentiation. We provide evidence supporting this hypothesis by comparing murine prostatic growth in a tissue reconstitution assay with cell recombinants of different basal-to-luminal ratios. Additionally, in organoid culture, hybrid organoids derived from adjacent basal and luminal cells showed reduced basal stem cell activities, suggesting contact inhibition. Importantly, removal of adult luminal cells in vivo via either an inducible Cre/loxP-Dre/rox dual-lineage-tracing system or orthotopic trypsin injection led to robust reactivation of basal stem cell activities, which acts independent of androgen. These data illustrate the prostate organ as a distinctive paradigm where cell contact from differentiated daughter cells restricts adult stem cell multipotency to maintain the steady-state epithelial architecture.

SUBMITTER: Horton C

PROVIDER: S-EPMC6826291 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Luminal-contact-inhibition of epithelial basal stem cell multipotency in prostate organogenesis and homeostasis.

Horton Corrigan C Liu Yueli Y Yu Chuan C Xie Qing Q Wang Zhu A ZA

Biology open 20191001 10

Prostate epithelial basal cells are highly plastic in their luminal differentiation capability. Basal stem cells actively produce luminal cells during organogenesis, but become restricted in the adult prostate unless receiving oncogenic or inflammatory stimuli. Given that the number of luminal cells increases relative to basal cells through development and that equilibrium is reached in the adulthood, we hypothesize that a negative-feedback mechanism exists to inhibit basal-to-luminal differenti ...[more]

PMID: 31540905

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Project description:ImportanceLuminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct and clinically important in predicting response to therapy. These subtypes have not been described in metastatic prostate cancer.ObjectivesTo identify clinical and molecular correlates of luminal and basal subtypes in metastatic castration-resistant prostate cancer (mCRPC) and investigate differences in survival, particularly after treatment with androgen-signaling inhibitors (ASIs).Design, setting, and participantsIn this cohort study, a retrospective analysis was conducted of 4 cohorts with mCRPC (N = 634) across multiple academic centers. Treatment was at the physicians' discretion. Details of the study cohorts have been published elsewhere between 2016 and 2019. Data were analyzed from March 2018 to February 2021.Main outcomes and measuresThe primary clinical end point was overall survival from the date of tissue biopsy/molecular profiling. Luminal and basal subtypes were also stratified by postbiopsy ASI treatment. The primary molecular analyses included associations with small cell/neuroendocrine prostate cancer (SCNC), molecular pathways, and DNA alterations.ResultsIn the 634 patients, 288 (45%) had tumors classified as luminal, and 346 (55%) had tumors classified as basal. However, 53 of 59 (90%) SCNC tumors were basal (P < .001). Similar to primary prostate cancer, luminal tumors exhibited overexpression of AR pathway genes. In basal tumors, a significantly higher rate of RB1 loss (23% basal vs 4% luminal; P < .001), FOXA1 alterations (36% basal vs 27% luminal; P = .03) and MYC alterations (73% basal vs 56% luminal; P < .001) were identified. Patients with basal tumors had worse overall survival compared with those with luminal tumors only in patients treated with an ASI postbiopsy (East Coast Dream Team: hazard ratio [HR], 0.39; 95% CI, 0.20-0.74; P = .004; West Coast Dream Team: HR, 0.57; 95% CI, 0.33-0.97; P = .04). Among patients with luminal tumors, those treated with an ASI had significantly better survival (HR, 0.27; 95% CI, 0.14-0.53; P < .001), whereas patients with basal tumors did not (HR, 0.62; 95% CI, 0.36-1.04, P = .07). The interaction term between subtype and ASI treatment was statistically significant (HR, 0.42; 95% CI, 0.20-0.89; P = .02).Conclusions and relevanceThese findings represent the largest integrated clinical, transcriptomic, and genomic analysis of mCRPC samples to date, and suggest that mCRPC can be classified as luminal and basal tumors. Analogous to primary prostate cancer, these data suggest that the benefit of ASI treatment is more pronounced in luminal tumors and support the use of ASIs in this population. In the basal tumors, a chemotherapeutic approach could be considered in some patients given the similarity to SCNC and the diminished benefit of ASI therapy. Further validation in prospective clinical trials is warranted.

Dataset Information

Luminal-contact-inhibition of epithelial basal stem cell multipotency in prostate organogenesis and homeostasis.

Publications

Luminal-contact-inhibition of epithelial basal stem cell multipotency in prostate organogenesis and homeostasis.

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