Role of mitochondrial metabolism in malignant mesothelioma aggressiveness

Malignant mesothelioma is an aggressive cancer that affects mesothelial cells, which form protective linings around internal organs. It is associated with poor prognosis due to its late-stage diagnosis and the limited efficacy of standard treatments such as surgery, chemotherapy and radiation therapy. As a result, the overall life expectancy is often around 12 months even when treated. Here, we explored the invasiveness of cancer in human malignant mesothelioma cell lines from a metabolic perspective to potentially identify biomarkers, aiming at enhancing tumor diagnosis and prognosis in clinical medicine and finding new druggable targets useful in therapy. We analyzed the differential expression of genes encoding mitochondrial proteins in primary epithelioid and primary sarcomatoid human malignant mesothelioma cell lines. Notably, there was a remarkable increase in the expression of long-chain acyl coenzyme A dehydrogenase (ACADL). Consistent with the results, sarcomatoid human mesothelioma cell lines characterized by higher cell migration/invasiveness, had more active fatty β-oxidation (FAO), electron transport chain activity and produced more ATP than epithelioid human mesothelioma cell lines. Since inhibition of FAO with etomoxir decreased cell migration, it suggests an important role of mitochondrial metabolism in sarcomatoid human mesothelioma cells' aggressiveness. Hence, FAO supports ATP production through electron transport chain activity, providing energy for cell migration/invasiveness in sarcomatoid mesothelioma tumors. In conclusion, these findings suggest that the evaluation of mitochondrial metabolism in malignant mesothelioma cell lines may be a potential biomarker, enabling the identification of tumors with heightened invasiveness and new potential therapy targets.