Unipd Research: discovering a mechanism that forms metastases in melanoma

08.11.2023

Melanoma is the deadliest form of skin cancer, mainly due to its high heterogeneity that drives tumor metastasis. Cell plasticity is the ability of cells to switch their phenotypic state. According to this phenotypic switching model, melanoma cells can switch their phenotype from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype.

The ability of melanoma cells to switch from one state to another depends on the expression of the microphthalmia-associated transcription factor (MITF). High levels of MITF stimulate and support the formation of more specialized tumor cells during their differentiated state but with less metastatic capacity. Low levels of MITF are associated with an undifferentiated state, which forms immature and not yet specialized cells but is characterized by its invasiveness and a greater propensity to form metastases.

A University of Padua Department of Biology research team, led by Prof Luigi Leanza, has shown that the protein Transglutaminase type 2 (TG2), known to be involved in celiac disease, also plays a key role in the regulation of melanogenesis and influencing the expression and MITF activities. Published as Transglutaminase Type 2-MITF axis regulates phenotype switching in Skin Cutaneous Melanoma in the international magazine Cell Death and Disease, the study received funding from the AIRC Foundation for cancer research.

Prof Leanza explains, “Our team has proven that the expression of TG2 is associated with a lower ability of cells to form metastases. In particular, we observed that TG2 can interact with MITF, thus supporting its ability to activate genes involved in both differentiation and pigmentation through the production of melanin. The consequence is a lower ability to form metastases. In the absence of TG2, MITF is unable to function and this causes a reduction in both pigmentation and differentiation and an increase in the size of metastases.”

The numerous applications of the results of this study, which for the first time linked the action of TG2 to one of the most important signaling pathways of melanoma cells, are promising for the treatment of metastatic melanoma.