OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression

Macrophages, which are highly plastic, can be polarized to Ml or M2 subtypes according to the diverse signals in complex microenvironment. Studies have shown the activation of YAP, an oncogenic transcriptional co-activator, increased macrophage recruitment. However, its role in macrophage polarization remains to be elucidated, especially in triple-negative breast cancer (TNBC) progression. Here we found TNBC cells increased YAP expression in macrophages, which depended on OTUD5-mediated deubiquitination and stabilization of YAP, then the high expression of YAP polarized macrophage to the M2-like phenotype. Moreover, the elevation of YAP in M2-like macrophage promotes the pro-metastatic potential of TNBC cells via MCP-1/CCR2 pathway. We also observed high expression of YAP in M2 macrophage was negatively related to survival. Collectively, our finding suggested the therapeutic strategy that targets YAP(+) M2 macrophage could be a novel option for TNBC treatment.

Automated summary

Studies have shown that the activation of YAP increases macrophage recruitment, but its role in macrophage polarization, especially in TNBC progression, is still unclear. TNBC cells were found to increase YAP expression in macrophages via OTUD5-mediated deubiquitination and stabilization, leading to polarization towards the M2-like phenotype. Additionally, high expression of YAP in M2-like macrophages was associated with pro-metastatic potential of TNBC cells through the MCP-1/CCR2 pathway, and negatively related to survival. This suggests that targeting YAP(+) M2 macrophages could be a novel therapeutic strategy for TNBC treatment.