Macrophagic S100A4 drives macrophage protumor activation and promotes tumor growth through controlling PPAR-? induction

The lipid-metabolism up-regulation-mediated M2 polarization provides tumor-associated macrophages (TAMs) with protumor phenotypes during tumor development and progression. However, how TAMs reprogram their lipid-metabolism responding to M2 activators remains unclear. Here, we report that S100A4 is a determinant of macrophage M2 polarization. We find that the growth of carcinoma grafts was impaired in myeloid S100A4-deficient mice. Coincidentally, ablating S100A4 in macrophages reduced their capability of macrophage into utilization utilize of exogenous fatty acids as their major energy source for oxidation. Mechanistic analysis demonstrates that the induction of PPAR-? responding to Th2 cytokine, IL-4, was halted in s100a4-deleted TAMs, as well as in bone marrow-derived macrophages, and as well as in Raw264.7 cells. Further molecular analyses reveal that CD36, downstream from S100A4-PPAR?, is the major effector for lipid uptake of S100A4+ macrophages. FurthermoreImportantly, higher levels of S100A4 is closely associated with tumor resistance to chemotherapy in murine models as well as poor prognosis of cancer patients in clinic . Our study thus suggests that blocking S100A4 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting PPAR-?-induction mediated gene up-regulation. Overall design: Protein-coding mRNA sequencing (RNA-seq) analysis of S100A4+ and S100A4- TAMs. There were three samples for each cell population.