A Mitochondrial Switch Promotes Tumor Metastasis

Abstract

Metastatic progression of cancer is associated with poor outcome, and here we examine metabolic changes underlying this process. Although aerobic glycolysis is known to promote metastasis, we have now identified a different switch primarily affecting mitochondria. The switch involves overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production. It provides a metastatic advantage phenocopied by partial ETC inhibition, another situation associated with enhanced superoxide production. Both cases 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.

Metabolism in cancer metastasis

“…The reactive oxygen species (ROS) generated by the mitochondria may activate SRK and PYK2, which support tumor progression. 45 outgrowth, elevated levels of peroxide are required for the process. However, once exceeding a threshold level, the intracellular reactive oxygen species become limiting to cancer progression by modifying biomolecules and inducing apoptosis.…”

“…Electron transport chain overload and partial electron transport chain inhibition promote reactive oxygendependent tumor cell migration, invasion, and metastasis. 45 …”

Cancer metabolism in space and time: Beyond the Warburg effect

“…How ever, ox ida tive mi to chon dr ial me tab o lism is cur rently emerg ing as an other ma jor reg u la tor of tu mor metas ta sis. Re cent works on breast can cer and melanoma mod els have re vealed that at least some metasta tic can cer cells have a high ox ida tive me tab o lism and that mi to chon dr ial me tab o lism in creases along with the pro gres sive ac qui si tion of metasta tic traits [11,132]. More over, mi to chon dr ial trans fer from stro mal to can cer cells has been shown to in crease the abil ity to metas ta size [182].…”

“…If high lev els of mi to chon dr ial ROS pro mote apop to sis and low lev els en sure cel lu lar home osta sis [190], in ter me di ate sub lethal lev els were shown to ac ti vate pro metasta tic sig nal ing path ways (in clud ing Src and Pyk2) [11] and to in crease cell tol er ance to stress [10,191,192]. Both a par tial in hi bi tion and an over load of the elec tron trans port chain re sult in elec tron leak and were shown to pro mote tu mor metas ta sis in a mtROS de pen dent way [11,193].…”

“…Meta bolic het ero gene ity can also be in ter preted in time, as can cer cells adapt their meta bolic ac tiv i ties ac cord ing to spe cific re quire ments bound to on go ing processes. A par a dig matic ex am ple of tem po ral in flu ences is metas ta sis for ma tion, dur ing which can cer cells un dergo se quen tial meta bolic re pro gram ming ac cord ing to the spe cific steps that are in volved in the metasta tic process, rang ing from de creased mi to chon dr ial res pi ra tion fol low ing early cell de tach ment [9] to higher mi to chon dr ial oxy gen con sump tion to pro mote mi gra tion and in va sion [10,11].…”