De novo steroidogenesis in tumor cells drives bone metastasis and osteoclastogenesis

Osteoclasts play a central role in cancer-cell-induced osteolysis, but the molecular mechanisms of osteoclast activation during bone metastasis formation are incompletely understood. By performing RNA sequencing on a mouse breast carcinoma cell line with higher bone-metastatic potential, here we identify the enzyme CYP11A1 strongly upregulated in osteotropic tumor cells. Genetic deletion of Cyp11a1 in tumor cells leads to a decreased number of bone metastases but does not alter primary tumor growth and lung metastasis formation in mice. The product of CYP11A1 activity, pregnenolone, increases the number and function of mouse and human osteoclasts in vitro but does not alter osteoclast-specific gene expression. Instead, tumor-derived pregnenolone strongly enhances the fusion of pre-osteoclasts via prolyl 4-hydroxylase subunit beta (P4HB), identified as a potential interaction partner of pregnenolone. Taken together, our results demonstrate that Cyp11a1-expressing tumor cells produce pregnenolone, which is capable of promoting bone metastasis formation and osteoclast development via P4HB. [Display omitted] •Osteotropic tumors express CYP11A1 and de novo synthetize the steroid pregnenolone•Intratumoral CYP11A1 promotes bone metastasis formation and tumor-induced osteolysis•Pregnenolone drives osteoclastogenesis and fusion of osteoclasts via P4HB molecule•Osteotropic human cancer cells produce pregnenolone and enhance osteoclastogenesis Sandor et al. show that CYP11A1-mediated de novo steroidogenesis in osteotropic tumor cells drives bone metastasis and osteoclastogenesis in both humans and mice. They identify pregnenolone, product of CYP11A1 activity, as a potential cancer-cell-derived regulator of osteoclastogenesis, able to stimulate the fusion of osteoclasts via interaction with the P4HB molecule.