巨噬细胞的极化异质性对卵巢癌腹水的分子调控机理

血管通透性改变是影响卵巢癌腹水形成的重要因素，肿瘤相关巨噬细胞参与并调节该病理过程。抑制卵巢癌巨噬细胞可减少腹水，却并发严重的颜面部和肢端水肿。该现象提示巨噬细胞对血管通透性的调节存在异质性。我们前期研究支持该观点，并发现不同极化的巨噬细胞对血管通透性的作用迥异：M1亚型促进血管通透，而M2亚型保护血管屏障。明确调节血管通透性的极化特异性分子是研究巨噬细胞极化异质性对腹水调控的基础与前提。过去对大量混合细胞的转录组测序无法在单细胞层面研究异质性，我们采用单细胞测序在小鼠中成功证明卵巢癌巨噬细胞的极化异质性，且发现一些细胞粘附分子在不同极化巨噬细胞中的表达差异。本项目拟在细胞和动物模型中研究这些极化特异性细胞粘附分子对血管通透性的调节功能及机理，并在临床样本中探讨卵巢癌巨噬细胞的极化异质性、调控机制及其与腹水生成的关系。本研究将为卵巢癌腹水的临床治疗和以巨噬细胞为靶标的免疫治疗提供新策略。

Change of vascular permeability is a key factor in ascites production in ovarian cancer, in which tumor-associated macrophages play a crucial role. Targeting macrophages, on one hand, abrogated the formation of ascites, indicating a rescue of vascular leakage; on the other hand, resulted in an increase of permeability, shown as edema, suggesting the heterogeneity of macrophage-mediated vascular permeability. Our previous findings revealed that differentially polarized macrophages have disparate regulatory impact on vascular permeability, i.e., M1-macrophages induce permeability, whereas M2-macrophages protect the vascular barrier. To identify polarization-specific molecules that regulate vascular permeability is the foundation and prerequisite for the study of ascites regulation by the heterogeneity of macrophage polarization. RNA-seq studies in the past using bulk samples were unable to dissect the heterogeneity on the single-cell level. Thus, using recently developed single-cell RNA-seq technique we have demonstrated the heterogeneity in macrophage polarization in murine ovarian cancer model and identified certain cell adhesion molecules (CAMs) being differentially expressed in a polarization-specific manner. This project aims to determine the function and molecular mechanism of the CAMs in regulating vascular permeability using cellular and animal models. Also, we aim to study the heterogeneity of macrophages in ovarian cancer patient samples and its regulating mechanism on vascular permeability, as well as its relevance to ascites production. This project will provide new therapeutic strategies to treat ascites and macrophage-targeting immunotherapies.