Mitochondrial metabolism promotes metastatic progression.

Introduction. It is broadly accepted that tumor cells rewire metabolic fluxes in order to promote cell proliferation and resistance to apoptosis. However, the specific impact of metabolism on metastatic progression is still poorly characterized. Since most metastases are abnormally avid for glucose (which is the rationale for their clinical detection using FDG-PET), it is often assumed that mitochondrial metabolism is detrimental to metastatic progression. Still, mechanistic evidence is missing. In this study, we assessed the specific contribution of mitochondrial metabolism on metastasis development. Methods. Several clones with increased invasive and metastatic potential were generated following in vitro (starting from human cervix adenocarcinoma SiHa cells) and in vivo (starting from B16F10 murine melanoma cells) selection. A complete metabolic on these clones characterization was performed for measuring oxidative and glycolytic metabolism, as well as redox status and mitochondrial mass. The specific contribution of cancer cell metabolism to metastasis was assessed by the use of specific metabolic inhibitors or modulators. Results and discussion. We identified that a mitochondrial switch, corresponding to an overload of the TCA cycle with preserved mitochondrial functions but increased mitochondrial superoxide production, promotes metastasis. This switch provided a metastatic advantage that was reproduced by moderate OXPHOS inhibition associated with a moderate increase of mitochondrial superoxide levels. Both conditions involved protein tyrosine kinase PTK2B/Pyk2 increased expression and Src activation as downstream effectors. Coherently, the complete blockade of mitochondrial respiration, as well as the specific scavenging of mitochondrial superoxide prevented cancer cell invasion. Finally, we report that antioxidants specifically targeting mitochondria inhibit metastatic dissemination from primary murine and human tumors in mice. Conclusion. Two different events (i.e., OXPHOS overload and moderate OXPHOS inhibition) promote superoxide-dependent tumor cell metastasis. Overall, this work demonstrates the central role of mitochondrial superoxide generation in the pathogenesis of metastasis and the potential impact of its scavenging for metastasis prevention.