Human bone marrow adipocytes drive prostate cancer bone metastasis progression via lipid-mediated induction of Angiopoietin-like 4

Bone is the predominant metastatic site in advanced prostate cancer (PCa), and the role of bone marrow adipocytes (BMAds) which constitute over 70% of adult marrow remains poorly understood. Herein, we developed a physiologically relevant 3D culture model using primary human BMAds from red hematopoietic rich-areas (rBMAds). Using this model, we show that rBMAds engage in metabolic crosstalk with PCa cells by releasing free fatty acids (FFAs) through a non-canonical lipolytic pathway. These FFAs are taken up by PCa cells, and induce a transcriptional reprogramming that promotes motility. Among the responsive genes, Angiopoietin like 4 (ANGPTL4) is the most upregulated via a Peroxisome proliferator-activated receptor γ (PPARγ)-dependent mechanism, and its silencing abolishes the rBMAd-driven migratory and invasive phenotype. In bone metastases of patients with PCa, high ANGPTL4 levels correlated with poor survival. Together, our findings uncover a novel adipocyte-tumor interaction and identify ANGPTL4 as a key mediator and potential therapeutic target in bone-metastatic PCa.