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

Authors:
  • YZYongkang Zou
    Yongkang Zou
  • AWAndrea Watters
    Andrea Watters
  • NCNan Cheng
    Nan Cheng
  • CPCaroline E. Perry
    Caroline E. Perry
  • KXKe Xu
    Ke Xu
  • GAGretchen M. Alicea
    Gretchen M. Alicea
  • EBEzra Baraban
    Ezra Baraban
  • PRPulak Ray
    Pulak Ray
  • ANAnupma Nayak
    Anupma Nayak
  • XXXiaowei Xu
    Xiaowei Xu
  • MHMeenhard Herlyn
    Meenhard Herlyn
Open Access
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Abstract
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 γ (PPARγ) 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 PPARγ in brain metastatic cancer cells. PPARγ 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 PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis.Significance:Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.This article is highlighted in the In This Issue feature, p. 1631