Biology and pathologies of melanocytes: From skin pigmentation to melanoma

Because of intrinsic resistance or secondary resistance that can develop following treatment, the best way to treat melanoma is still its early detection, thereby showing the need to identify melanoma predisposing genes and at-risk patients to adapt their monitoring.

Our team is working in collaboration with the Institut Gustave Roussy in Paris to identify melanoma predisposing genes. We have discovered a mutation in the transcription factor MITF (p.E318K), the master gene of melanocyte homeostasis. This mutation confers to carriers a 5 times higher risk of developing melanoma. Importantly, this work has led to new national recommendations for dermatological follow-up. Our team continues to study the role of MITF in melanocyte biology and melanoma.

Our work has demonstrated that MITF plays a key role in cellular plasticity, a process that allows melanoma cells to adapt to their microenvironment and escape the effect of treatments.

Our team has pioneered the field of melanoma cell plasticity by demonstrating that high expression of MITF is associated with proliferative cells while low expression of MITF is associated with cells with an invasive phenotype. This phenotypic plasticity is used by tumor cells to evade treatment, which leads to recurrence. In collaboration with the Dermatology Department of Nice University Hospital (CHU), we have recently shown that MITF can regulate the anti-tumor immune response. Our team is working to better understand the mechanisms of this phenotypic plasticity, with a focus on epigenetic processes, to identify effective and long-lasting treatments.

Our work has led to the discovery of new molecules that regulate pigmentation and that are being exploited by industrial partners to improve the quality of life of individuals suffering from hyperpigmentation.

Although pigmentary defects are not fatal, they can have a very important psychological impact because the color of our skin is the first image we offer to the outside world. The transcription factor MITF plays a key role in the regulation of skin pigmentation. The identification of the molecular events that regulate its expression and that of its target genes has led to a better understanding of the mechanisms of skin pigmentation and to the identification of therapeutic targets, some of which are being exploited by industrial partnerships.

The etiology and genetics of uveal melanoma are different from cutaneous melanoma. At the metastatic state, uveal melanomas are highly refractory to existing treatments. 90% of patients are at a therapeutic dead end.

Our team uses state-of-the-art techniques (transcriptomics, proteomics, epigenomics, single cell sequencing) to better understand the progression of uveal melanoma. In collaboration with the ophthalmology department of Nice University Hospital, our team has recently demonstrated the existence of intratumoral heterogeneity in primary uveal melanomas. This study has identified molecular signatures that can predict the evolution of primary uveal melanomas and therapeutic targets that are currently being studied and that may be useful in the clinic to improve the survival of patients with uveal melanoma.