Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading 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 glial 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 act as donors of PPAR gamma activators to the invading cancer cells. In clinical samples, PPAR gamma signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPAR gamma antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic 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. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPAR gamma signaling. This protumor effect of PPAR gamma in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPAR gamma has diverse functions at different stages of cancer development.