CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer

Background Triple-negative type of breast cancer (TNBC) has limited therapeutic options and frequently metastasizes, leading to low survival rates. Oxidative phosphorylation (OXPHOS) is a driver of TNBC metastasis, but the signaling underlying this metabolic change is poorly understood. Methods We performed metabolic assays and assessed migratory and metastatic potential in cells with manipulated CDCP1/mitochondrial Src signaling. Results We show that the pro-metastatic cell surface protein CUB-domain containing protein 1 (CDCP1) activates Src kinase localized in mitochondria, which potently induces OXPHOS and TNBC migration. Genetic targeting of either CDCP1 or mitochondrial Src, as well as pharmacological inhibition of Src reduce OXPHOS in vitro. We further show that mitochondrial Src increases OXPHOS by stimulating Complex I activity in the electron transport chain. Importantly, rescuing Complex I activity in cells devoid of CDCP1/mitochondrial Src signaling restores both OXPHOS and migration. We also provide evidence that NAD + pool generated by Complex I is contributing to the observed migratory phenotype. Lastly, we determined that inhibiting mitochondrial Src reduces metastasis in TNBC cells. Conclusions Both CDCP1 and mitochondrial Src represent potential therapeutic targets to inhibit OXPHOS-mediated TNBC metastasis.