Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis

Menée à l'aide de lignées de cybrides, de xénogreffes sur des modèles murins ainsi que d'échantillons tumoraux et d'échantillons tissulaires normaux provenant de patients atteints d'un mélanome de stade avancé, cette étude met en évidence un mécanisme par lequel des mutations pathogènes au niveau de l'ADN mitochondrial inhibe le développement de métastases en bloquant l'entrée des cellules cancéreuses dans la circulation sanguine

Résumé en anglais

Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood. Pathogenic mtDNA is tolerated in melanoma growth but inhibits metastasis by blocking bloodstream entry.