The noncanonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages, and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastasis and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.Significance: This study establishes host-derived Wnt5a, expressed by peritoneal mesothelial cells and adipocytes, as a primary regulator of ovarian cancer intraperitoneal metastatic dissemination and identifies Fgr kinase as novel target for inhibition of metastasis.

中文翻译：

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宿主 Wnt5a 增强卵巢癌转移的微环境调节。

在患有卵巢癌的女性腹水中发现了高浓度的非经典 Wnt 配体 Wnt5a。在这项研究中，我们阐明了 Wnt5a 在卵巢癌转移中的作用。Wnt5a促进卵巢肿瘤细胞与腹膜间皮细胞的粘附以及迁移和侵袭，导致腹膜外植体的定植。卵巢肿瘤微环境的宿主成分，特别是腹膜间皮细胞和内脏脂肪，分泌Wnt5a。条件性敲除宿主 WNT5A 显着减少腹膜转移肿瘤负担。WNT5A 敲除小鼠中形成的肿瘤具有细胞毒性 T 细胞升高、M1 巨噬细胞增加和 M2 巨噬细胞减少，表明宿主 Wnt5a 促进免疫抑制微环境。Src 家族激酶 Fgr 被确定为 Wnt5a 的下游效应子。这些结果强调了之前未报道的宿主表达的 Wnt5a 在卵巢癌转移中的作用，并表明 Fgr 作为抑制卵巢癌转移进展的新靶点。意义：本研究建立了由腹膜间皮细胞和脂肪细胞表达的宿主衍生的 Wnt5a，如卵巢癌腹膜内转移扩散的主要调节因子，并将 Fgr 激酶确定为抑制转移的新靶点。