Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

SUMMARY Vitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions, including differentiation in many cell types. The prostate gland is hormonally regulated, requiring steroids for proliferation and terminal differentiation of secretory luminal cells. Vitamin D deficiency is associated with higher risk of lethal prostate cancer with an aggressive dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation homeostasis. To determine regulation of prostate epithelial differentiation by vitamin D status, patient-derived benign prostate epithelial organoids were maintained in vitamin D deficient (vehicle) or sufficient (10 nM 1,25-dihydroxyvitamin D) conditions and assessed by phenotype and single cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation of lineage-committed cells by inhibiting canonical Wnt activity and Wnt family member DKK3. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus these findings further link vitamin D deficiency to lethal disease.