LAUSR

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 (PPAR gamma 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 PPAR gamma in brain metastatic cancer cells. PPAR gamma 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 PPAR gamma activators to the invaded cancer cells. In clinical samples, PPAR gamma signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPAR gamma antagonist significantly reduces brain metastatic burden in vivo. Our study clarifies a pro-metastatic role for PPAR gamma signaling in cancer metastasis in the lipid rich brain microenvironment and argues for the use of PPAR gamma blockade to treat brain metastasis.