Abstract 6280: Vitamin D enhances luminal differentiation of prostate organoids more than androgens

Abstract

Abstract Background: Prostate Cancer (PCa) is a prevalent disease affecting over two million men worldwide. Vitamin D is a fat-soluble hormone that is well-known for its role in the maintenance of strong bones and has anti-cancer effects in prostate cancer. Vitamin D is synthesized in the skin in response to sun exposure and may be supplemented with diet. However, since melanin hinders this synthesis many African Americans are deficient in vitamin D. Vitamin D circulates as 25-hydroxyvitamin D3 (25D) and 25-dihydroxyvitamin D3 (1,25D). Hydroxylation of 25D by the kidney or within tissues forms the active hormone 1,25D. 1,25D binds the vitamin D receptor (VDR), a steroid transcription factor. Androgens are the main regulatory hormones involved in prostate growth and differentiation. Epithelial differentiation is the process in which progenitor or stem cells become specialized cells, such as basal or luminal. In the prostate, luminal epithelial cells are the most differentiated and are the origin of PCa. We used mouse prostate organoids to replicate the differentiation process in vitro and to help identify the role of 1,25D on epithelial differentiation in the presence and absence of other androgens. Methods: Primary mouse prostate cells were isolated from dorsal lateral lobes and grown as organoids. Over two weeks, we treated these organoids with concentrations of 1,25D and androgen (dihydrotestosterone, DHT). The four treatment groups were control, 1,25D only, DHT only and 1,25D+DHT. Organoids were imaged and analyzed for number, size and phenotype. Phenotypes were identified as luminal, acinar, or solid. Results: Luminal phenotypes were more prevalent in 1,25D conditions compared to control or DHT alone. The number, size and percent of luminal organoids was highest in 1,25D + DHT compared to all other groups. Ongoing studies include examination of prostate organoids from mice with a vitamin D-deficient diet and staining of the organoids for differentiation markers. Conclusions/Significance: We observed that 1,25D enhanced luminal epithelial differentiation in mouse prostate organoids. These findings suggest that chronic vitamin D deficiency may increase risk of aggressive prostate cancer, due to decreased epithelial differentiation. This has implications for the disparity of aggressive PCa observed in African American men who have lower vitamin D levels compared to their white counterparts. Citation Format: Oscar Fernando Cerna, Larisa Nonn, Mike Schlicht, Kirty Krieger. Vitamin D enhances luminal differentiation of prostate organoids more than androgens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6280.