The impact of malignant ascites on macrophage polarization in ovarian cancer peritoneal carcinomatosis

Abstract

Peritoneal carcinomatosis of epithelial ovarian cancer (EOC), driven by both the endogenous malignancy of the ovarian cancer cells and the exogenous sharping of the tumor microenvironment, is highly associated with an extremely poor prognosis among EOC patients. Clinical evidence disclosed that EOC possesses precedential metastatic tropism towards the adipose-rich omentum and accumulates lipid-enriched ascitic fluid with this progress, suggesting the malignant ascites microenvironment played a pivotal role in facilitating tumor progression and metastasis. Previous studies have suggested that lymphocyte adaptation in the ascites microenvironment not only impairs cytotoxic abilities of T cells and natural killer (NK) cells, but also exhibits tumor-supporting actions. Macrophages, the most abundant immune cells within the tumor microenvironment (TME), are often polarized into tumor-associated macrophages (TAMs). Recently, it has been revealed that TAMs fall on a dynamic spectrum of phenotypes, skewing to M2-like with trophic functions instead of M1-like with anti-tumoral properties, in the promotion of tumor growth, invasiveness, angiogenesis, metastasis and immunosuppression to facilitate tumor progression. TAMs with a high ratio of M2/M1 are therefore correlated to the poor prognosis of EOC and play a critical role in metastatic progression in numerous human cancers. However, the fundamental mechanisms inherent to TAMs polarization in the ascites microenvironment and TAMs-mediated metastatic progression remain poorly understood. In this study, functional and mechanistic characterizations of how the malignant ascites microenvironment contributes to macrophage-mediated pro-metastatic niche formation are being assessed. Results showed that RHOA-GTPase-Hippo/YAP1 signalling regulates M2-like TAMs accumulation and that targeting the Hippo/YAP1 pathway reverses M2-like TAMs polarization to an M1-like phenotype, combating peritoneal carcinomatosis of EOC. I found that the abundant levels of polyunsaturated fatty acids (PUFAs) in malignant ascites increase oxidative phosphorylation (OXPHOS) metabolism and inactivate RHOA-GTPase, leading to YAP1 cytoplasmic retention in macrophages. Abolish Yap1 in macrophages in vivo, causing high M2/M1 TAMs polarization, suppressing CD8+ T cell infiltration and aggravating peritoneal metastatic progression. Consistently, upregulated MST1 expression and the loss of nuclear YAP1 were observed in metastatic lesions and ascites spheroids in EOC. Pharmaceutical inhibition of MST1/2 restored nuclear YAP1 expression, facilitating M2-like TAMs polarization toward the tumoricidal M1 phenotype and promoting antitumor immunity. Hence, targeting Hippo/YAP1 signalling can prevent peritoneal carcinomatosis in EOC. This study elucidates the mechanism underlying the lipid-enriched ascites microenvironment that governs M2-like TAMs polarization in peritoneal carcinomatosis. Abundant PUFAs in malignant ascites suppress RHOA-GTPase-YAP1 signalling and OXPHOS metabolism, facilitating M2-like TAMs polarization. Pharmacological targeting of MST1/2 combats peritoneal carcinomatosis by reprogramming M2-like TAMs to M1-like TAMs.