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.

Assessment of ferroptosis inducers and Nrf2 inhibitors as radiosensitisers in 2D and 3D breast cancer cell cultures

“…Interestingly, a parallel phenomenon has very recently been described in TNBC whereby cancers show marked heterogeneity with respect to ferroptosis markers (Yang et al , 2023). Similarly, ferroptotic heterogeneity has also been reported in melanoma (Lin et al , 2022) which mirrors observations for heterogeneity of apoptosis inducers in breast cancer cells and other tumour cell types (Cross et al , 2008, Spencer et al , 2009). Further research is necessary to determine the possibility and precise processes by which ferroptosis activation and Nrf2 inhibition can decrease the radio-resistance of hypoxic cancer cells in various cancer situations, and to identify metabolic signatures of ferroptosis-sensitive vs. resistant populations.…”

Cellular metabolism: A key player in cancer ferroptosis

“…Lactate is a metabolite of glycolysis, and mucosal melanoma cells can take up extracellular lactate through mononuclear transport carriers, thereby increasing PPP pathway signaling and upregulating ferroptosis‐related GPX4 and FSP1 expression. In addition, lactate induces an increase in the intracellular levels of NADH, NADPH and GSH, leading to the resistance of tumor cells to ferroptosis [ 30 ]. In addition, lactate can activate the hydroxycarboxylic acid receptor 1 (HCAR1)/monocarboxylate transporter 1 (MCT1)‐sterol regulatory element‐binding protein 1 (SREBP1)‐stearoyl‐coenzyme A desaturase‐1 (SCD1) signaling pathway to induce monounsaturated fatty acid (MUFA) generation, thereby inhibiting the ferroptosis of tumor cells [ 31 ].…”

Experimental Models for Rare Melanoma Research—The Niche That Needs to Be Addressed

“…The cells presented two heterogeneous phenotypes, adherent (with a spindle-like morphology) and suspension cells (with a round shape, and a higher metastatic capacity), respectively. These cell lines were used to investigate the possible link between cancer heterogeneity and metastasis in melanoma [ 58 ]. Shi et al established the MM9H-1 cell line from the tumor tissue derived from a patient with MM.…”