CD95L Cell Surface Cleavage Triggers a Prometastatic Signaling Pathway in Triple-Negative Breast Cancer

摘要: Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this is not understood. Here we report that serum levels CD95L are higher in TNBC patients compared to other cancer patients. Metalloprotease-mediated cleavage expressed by endothelial cells surrounding tumors generates gradient promotes cell motility, due formation an unconventional CD95-containing receptosome termed motility-inducing signaling complex. Formation complex was instrumental Nox3-driven ROS generation. Mechanistic investigations revealed Yes-Orai1-EGFR-PI3K pathway triggered migration exposed CD95L. Our findings establish pro-metastatic function metalloprotease-cleaved triple-negative cancers, revisiting its role carcinogenesis.