Polyunsaturated Fatty Acids from Astrocytes Activates PPAR Gamma Signaling in Cancer Cells to Promote Brain Metastasis

Brain metastasis, the most ominous form of melanoma and carcinoma, is the consequence of favorable interactions between the invaded cancer cells and the brain cells. Peroxisome proliferator-activated receptor gamma (PPARɣ) has ambiguous functions in cancer development and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glia cells, activate PPARɣ in brain metastatic cancer cells. PPARɣ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that acts as ‘donors’ of PPARɣ activators to the invaded cancer cells. In clinical samples, PPARɣ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARɣ antagonist significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPARɣ signaling in cancer metastasis in the lipid rich brain microenvironment and argues for the use of PPARɣ blockade to treat brain metastasis. RNA-seq analysis of high and low brain metastatic cell lines cultured alone or with presence of astrocytes.