Single-cell analyses unravel cell type-specific responses to a vitamin D analogue in prostatic precancerous lesions [scRNA-Seq]

Epidemiological data have linked vitamin D deficiency to the onset of various cancers, including prostate cancer, and although in-vitro studies have demonstrated anti-cancer activities for the vitamin, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically-engineered mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analogue with reported anti-cancer activities, and comprehensively analyzed its effects on various cell types in such lesions. We show that this analogue induces apoptosis in senescent PINs and normalizes extracellular matrix remodeling by stromal fibroblasts in an epithelial VDR-dependent manner. Furthermore, it reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells in an epithelial VDR-independent manner. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal epithelial cells, expressing Krt4 and Tacstd2 (termed luminal-C) with enhanced interferon signature, is lost by such a treatment, anti-apoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of prostatic precancerous lesions and the microenvironment to the vitamin D analogue, and shed light on mechanisms that limit treatment's efficacy. Overall design: 2 samples were analyzed, and prepared from dissociated prostates of vehicle- and Gemini-72-treated Pten(i)pe-/- mice.