Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells

Abstract

Ex vivo stem cell self-renewal and maintenance is supported by absence of serum-derived mitogens. In the present study, we sought to elucidate the proteomes of stem-like cells grown in serum-free media across a panel of high-grade serous ovarian cancer cell lines, which encompass a gradient from epithelial, intermediate and mesenchymal cell phenotypes to recapitulate the heterogeneity of the disease. MaxQuant-based label-free quantification of proteins identified that despite their different cellular and molecular architectures, all phenotypes exhibited mitochondria- and stemness-related pathways under conditions of serum starvation, although the specific proteins involved were discrete to each phenotype. This suggests that common cellular programs in a disease can be mediated through variable biological networks that generates molecular heterogeneity. We further explored if these pathways are inter-related, co-regulated or just incidentally associated in response to an environment depleted of growth factors and mitogens. Irrespective of their phenotype, cell lines on serum-starvation displayed an increased amount of mitochondrial DNA, mitochondrial biogenesis and mitochondrial activity with a switch from glycolysis to oxidative phosphorylation fuelled by the fatty acid oxidation. Ultra-structural studies implicated this metabolic fluctuation was regulated by dynamic mitochondrial remodelling. This also led us to explore a possible therapeutic strategy of targeting mitochondrial function to restrict tumor regenerative potential and disease recurrence. Conclusively, these new avenues contribute to a more comprehensive understanding of ovarian cancer.