Vitamin D sufficiency enhances differentiation of patient-derived prostate epithelial organoids

Abstract

Vitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions. The prostate gland is hormonally regulated, requiring steroids for proliferation and differentiation of secretory luminal cells. Vitamin D deficiency is associated with an increased risk of lethal prostate cancer, which exhibits a dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation. To determine vitamin D regulation of prostatic epithelial differentiation, patient-derived benign prostate epithelial organoids were grown in vitamin D-deficient or -sufficient conditions. Organoids were assessed by phenotype and single-cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation by inhibiting canonical Wnt activity and suppressing Wnt family member DKK3. Wnt and DKK3 were also reduced by vitamin D in prostate tissue explants by spatial transcriptomics. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus findings further link vitamin D deficiency to lethal disease.

Milk Intake in Early Life and Later Cancer Risk: A Meta-Analysis

“…Concerning prostate cancer, it is notable that calcium, unlike its anti-carcinogenic effect on breast and colorectal cancers, may rather increase prostate cancer risk by inhibiting the synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, also known as calcitriol), and the active metabolite of vitamin D3 that suppresses cell proliferation in the prostate [ 1 ]. Adolescent milk intake increases circulating IGF-1 levels during the critical period of prostate development and growth, thereby promoting prostate cell proliferation and enhancing the survival of partially transformed cells which would otherwise be forced into apoptosis [ 47 ].…”

“…Dairy products are widely consumed worldwide, and they contain diverse components that are shown to influence cancer risk. The most notable one is calcium, as a high calcium intake is shown to suppress prostate cancer proliferation [ 1 , 2 ], while promoting colorectal epithelial cell differentiation and apoptosis [ 3 ]. Dairy products also contain insulin-like growth factor-I (IGF-I) [ 4 ], and for adults, a high dairy intake is associated with an increase in IGF-I concentration [ 5 ], stimulating cell proliferation.…”

Vitamin D treatment induces in vitro and ex vivo transcriptomic changes indicating anti‐tumor effects

“…Our ex vivo dataset adds to a small number of studies demonstrating gene expression changes in patient-derived organoids treated with vitamin D. [25][26][27] HT12 microarray used to assess gene expression and paired results pooled to assess for in vitro responses to calcitriol. Human intestinal organoids were derived from normal mucosa from three patients and treated with calcitriol for 24 h. Organoids from six wells were pooled for each RNA sample, and HT12 microarray used to assess gene expression and paired results pooled to assess for in vitro responses to calcitriol.…”

Harnessing the Utility of Ex Vivo Patient Prostate Tissue Slice Cultures

“…Briefly, a 5 or 10 mm core of fresh tissue is stabilized in agar and mounted in a precision slicer, generating ~300 µm slices, which are quickly placed into culture. The majority of studies utilize titanium mesh inserts to mount slices within 6-well tissue culture plates ( 3 , 6 , 8 – 12 ). The TS on a titanium mesh rotates on an angle to dip the TS in and out of media, driving capillary action for equivalent distribution of media and exposure to gases.…”