Human bone marrow adipocytes drive prostate cancer bone metastasis progression via lipid-mediated induction of Angiopoietin-like 4
Hernandez, M.; Shin, S.; Rengel, D.; Dauvillier, S.; Geoffre, N.; Valle, C.; Taccini, A.; Moutahir, M.; Bertrand-Michel, J.; Reina, N.; Muller, C.; Attane, C.
Show abstract
Bone is the main metastatic site in advanced prostate cancer (PCa) and contains bone marrow adipocytes (BMAds), which account for more than 70% of adult bone marrow. However, their role in the progression of PCa metastases remains poorly understood. Herein, we developed a physiologically relevant 3D culture model using primary human BMAds from red hematopoietic rich-areas (rBMAds) and we showed that rBMAds engage in metabolic crosstalk with PCa cells. Specifically, rBMAds release free fatty acids (FFAs) through a non-canonical lipolytic pathway and these FFAs are taken up by PCa cells inducing a transcriptional reprogramming that promotes motility. Among the responsive genes, Angiopoietin like 4 (ANGPTL4) is the most upregulated via a peroxisome proliferator-activated receptor {gamma}-dependent mechanism, and its silencing abolishes the rBMAd-driven migratory and invasive phenotype. In bone metastases of patients with PCa, high ANGPTL4 levels correlate 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.
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