A mitochondrial switch promotes tumor metastasis

Cancer metastasis is of dismal prognosis. Although aerobic glycolysis could promote metastasis, here we identified a different switch primarily affecting mitochondria. It corresponds to an overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production. The switch provided a metastatic advantage phenocopied by partial ETC inhibition, another situation associated with enhanced superoxide production. Both involved protein tyrosine kinases Src and Pyk2 as downstream effectors. Thus, two different events, ETC overload and partial ETC inhibition, promote superoxide-dependent tumor cell migration, invasion, clonogenicity and metastasis. Consequently, specific scavenging of mitochondrial superoxide with mitoTEMPO blocked tumor cell migration and prevented spontaneous tumor metastasis in murine and human tumor models.