Macrophagic S100A4 drives macrophage protumor activation and promotes tumor growth through controlling PPAR-γ 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-γ 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-PPARγ, 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-γ-induction mediated gene up-regulation. Protein-coding mRNA sequencing (RNA-seq) analysis of S100A4+ and S100A4- TAMs. There were three samples for each cell population.

在肿瘤发生与进展过程中，脂质代谢上调介导的M2极化会赋予肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）促肿瘤表型。然而，肿瘤相关巨噬细胞如何响应M2极化激活剂重编程自身脂质代谢，目前仍不明确。本研究证实S100A4是巨噬细胞M2极化的关键调控因子。我们发现，髓系S100A4敲除小鼠的癌移植瘤生长受到显著抑制。与之相一致的是，巨噬细胞中敲除S100A4会削弱其利用外源性脂肪酸作为主要氧化供能来源的能力。机制分析显示，在S100A4缺失的TAMs、骨髓来源巨噬细胞以及Raw264.7细胞中，Th2细胞因子白细胞介素4（IL-4）诱导的过氧化物酶体增殖物激活受体γ（PPAR-γ）表达被阻断。进一步的分子分析表明，位于S100A4-PPARγ通路下游的CD36是S100A4阳性巨噬细胞脂质摄取的核心效应分子。此外，值得注意的是，在小鼠肿瘤模型中，S100A4高表达与肿瘤化疗耐药密切相关；临床队列数据也显示，癌症患者体内S100A4高表达与不良预后显著相关。综上，本研究提示，阻断S100A4可通过抑制PPAR-γ诱导介导的基因上调，将巨噬细胞重编程为抗肿瘤表型，该策略有望成为肿瘤治疗的新方案。本研究针对S100A4阳性与S100A4阴性的TAMs开展了编码蛋白mRNA测序（RNA-seq）分析，每组细胞群体设置3个生物学重复样本。