Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis.

Abstract

Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the present study investigated the possible association between cancer heterogeneity and metastasis in melanoma. In total, two novel Chinese oral mucosal melanoma (COMM) cell lines, namely COMM-1 and COMM-2, were established for exploring methods into preventing the loss of cellular heterogeneity caused by long-term cell culture. Each cell line was grown under two different models of culture, which yielded two subtypes, one exhibited an adhesive morphology (COMM-AD), whereas the other was grown in suspension (COMM-SUS). Compared with the COMM-AD cells, the COMM-SUS cells exhibited higher metastatic capacities and autofluorescence. Further investigations indicated that the COMM-SUS cells exhibited metabolic reprogramming by taking up lactate produced by COMM-AD cells at increased levels to accumulate NADH through monocarboxylate transporter 1, whilst also increasing NADPH levels through the pentose phosphate pathway (PPP). Additionally, increased NADH and NADPH levels in the COMM-SUS cells, coupled with the upregulation of the anti-ferroptotic proteins, glutathione peroxidase 4 and ferroptosis suppressor protein 1, enabled them to resist ferroptotic cell death induced by oxidative stress during hematogenous dissemination. The inhibition of ferroptosis was found to substantially increase the metastatic capacity of COMM-AD cells. Furthermore, suppressing lactate uptake and impairing PPP activation significantly decreased the metastatic potential of the COMM-SUS cells. Thus, the present study on metabolic heterogeneity in COMM cells potentially provides a novel perspective for exploring this mechanism underlying cancer metastasis.