Impaired vitamin D signaling reveals neutrophils as key drivers of prostate cancer dissemination.

Prostate cancer (PCa)-related deaths are mainly due to metastasis. The increase in de novo metastatic hormone-naive PCa (mHNPCs) highlights the urgent need for biomarkers and treatment strategies. We report in a cohort of French PCa patients that the levels of vitamin D and of prostate-specific antigen, the progression biomarker used clinically, are negatively associated. However, the impact of vitamin D receptor (VDR) signaling on prostate tumorigenesis remains unclear. Mice with PTEN inactivation in prostatic epithelial cells (PECs) at adulthood (Pten(i)pe-/- mice) faithfully recapitulate the human disease. We showed that inactivation of PTEN and VDR in PECs promotes tumor aggressiveness. We demonstrate that VDR loss induces oxidative stress, which in turn enhances PECs proliferation. Moreover, CXCL5 overexpression in PTEN- and VDR-deficient PECs promotes neutrophil infiltration. Importantly, our data highlight elevated circulating neutrophil levels as a biomarker of PCa dissemination and show the potency of targeting neutrophil chemotaxis to reduce liver micrometastases. Overall, this work provides major insights into how vitamin D signaling slows down tumorigenesis and opens new avenues for therapeutic and diagnostic strategies for mHNPC.