Oxidative phosphorylation promotes primary melanoma invasion
Menée sur des poissons-zèbres et à l'aide d'échantillons tomoraux prélevés sur des patients atteints d'un mélanome primitif, cette étude met en évidence le rôle de la phosphorylation oxydative dans le processus d'invasion des cellules cancéreuses
Dermal invasion is a hallmark of malignant melanoma. Thought the molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, the early progression of non-invasive primary melanoma to an invasive state is poorly understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase A1 (Rps6ka1; RSK1) drives tumor invasion. Transcriptomic analysis of ribosomal protein S6 kinase A1-activated tumors identified metabolic changes, including up-regulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator activated receptor gamma (PPARG) coactivator 1 alpha (PPARGC1A), also known as PPARG coactivator-1α (PGC1α), has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens, PGC1α protein expression was found to be positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species scavenger scavenger receptor class A member 3 . PGC1α depletion modulated cellular processes associated with primary melanoma growth and invasion, including oxidative stress. These results support a role for PGC1α in mediating glutamine-driven oxidative phosphorylation to facilitate the invasive growth of primary melanoma.