COMMD3-mediated endosomal trafficking of HER2 inhibits the progression of ovarian carcinoma.

The dysregulated endocytic traffic of oncogenic receptors, such as the epidermal growth factor receptor family especially HER2, contributes to the uncontrolled activation of the downstream oncogenic signaling and progression of various carcinomas including 90% of ovarian carcinoma (OC). However, the key regulators in the intracellular trafficking of HER2 and their impacts for cancer progression remains largely unknown. In this study, through a genome-wide CRISPR/Cas9 screening for key genes affecting the peritoneal disseminated metastasis of OC, we identified a member of COMMD family, i.e., COMMD3, as a key regulator in the endosomal trafficking of HER2. In the high grade serous ovarian carcinoma (HGSOC) patients, the expression of COMMD3 is dramatically decreased in the peritoneal disseminated OC cells comparing with that in the primary OC 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 peritoneal 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 OC types and the design of new therapeutic strategy.