De novo steroidogenesis in tumor cells drives bone metastasis and osteoclastogenesis

Sandor, Luca and Huh, Joon and Benko, Peter and Hiraga, Toru and Poliska, Szilard and Dobo-Nagy, Csaba and Simpson, Joanna and Homer, Natalie and Mahata, Bidesh and Győri, Dávid Sándor (2024) De novo steroidogenesis in tumor cells drives bone metastasis and osteoclastogenesis. CELL REPORTS, 43 (3). No.-113936. ISSN 2211-1247

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Abstract

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 decreased number of bone metastases, but does not alter primary tumor growth and lung metastasis formation in mice. The product of CYP11A1 activity, pregnenolone strongly 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.

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