COMMD3-Mediated Endosomal Trafficking of HER2 Inhibits the Progression of Ovarian Carcinoma

The dysregulated endocytic traffic of oncogenic receptors, such as the EGFR family especially HER2, contributes to the uncontrolled activation of the downstream oncogenic signaling and progression of various carcinomas, including 90% of ovarian carcinoma. How-ever, the key regulators in the intracellular trafficking of HER2 and their impacts for cancer progression remain largely unknown. In this study, through a genome-wide CRISPR/Cas9 screening for key genes affecting the peritoneal disseminated metastasis of ovarian carcinoma, we identified a member of COMMD family, that is, COMMD3, as a key regulator in the endosomal trafficking of HER2. In the patients with high-grade serous ovarian carcinoma (HGSOC), the expression of COMMD3 is dramatically decreased in the peritoneal disseminated ovarian carcinoma cells comparing with that in the primary ovarian carcinoma cells. COMMD3 greatly inhibits the proliferation, migration, and epithelial-mesenchymal transition (EMT) of HGSOC cells, and dramatically suppresses the tumor growth, the formation of malignant ascites, and the perito-neal dissemination of cancer cells in the orthotopic murine model of HGSOC. Further transcriptome analysis reveals that silencing COMMD3 boosts the activation of HER2 downstream signaling. As a component in the Retriever-associated COMMD/CCDC22/ CCDC93 complex responsible for the recognition and recycling of membrane receptors, COMMD3 physically interacts with HER2 for directing it to the slow recycling pathway, leading to the attenuated downstream tumor-promoting signaling.Implications: Collectively, this study reveals a novel HER2 inactivation mechanism with a high value for the clinic diagnosis of new ovarian carcinoma types and the design of new thera-peutic strategy.

Automated summary

In this study, COMMD3 was identified as a key regulator in the endosomal trafficking of HER2, and its decreased expression was found to inhibit the proliferation, migration, and epithelial-mesenchymal transition of ovarian carcinoma cells. COMMD3 also suppressed tumor growth, formation of malignant ascites, and peritoneal dissemination of cancer cells. Further analysis revealed that COMMD3 interacts with HER2 to direct it to the slow recycling pathway and attenuate downstream tumor-promoting signaling.