Genetic tricks to track melanoma heterogeneity

Abstract

Melanoma is a malignant tumor that arises from pigment-producing cells in the skin, the melanocytes. With ultraviolet radiation from the sun or skin-tanning equipment as major triggers, melanoma is a major global health concern. Although early diagnosis supports successful treatment, advanced melanoma tumors harbor a mix of different cell populations that show variable resistance to treatment such as chemotherapy. The mechanisms underlying this variable resistance remain unclear, in part because longitudinal animal models of melanoma have been challenging to establish.Travnickova et al. have now decoded new tumor-supporting features of the mixed cell populations occurring in melanoma by harnessing genetic tools in the zebrafish, a pioneering model to study melanoma. The authors combined two genetic tricks available in zebrafish. First, they used a unique temperature-sensitive mutation in the gene mitfa that encodes a protein necessary for melanoma formation, which enabled the interruption of pigment cell maturation by shifting zebrafish to a slightly higher temperature. Second, the authors applied transgene-based labeling with the cre/loxP system to irreversibly mark cells with prior mitfa gene expression with fluorescently glowing proteins. The combination of these two techniques enabled the authors to (1) kill off melanoma tumor cells that depend on mitfa function to survive, and (2) watch the tumors then grow back when zebrafish were switched back to standard water temperature.After having validated this approach from several experimental angles, the authors then established that rare, so-called ‘persister cells’ are part of the original tumor and survive interruption of mitfa function. These persister cells then fueled the new growth of melanoma in the zebrafish, reminiscent of tumor relapse after treatment in patients. Importantly, the authors show that although persister cells do not require mitfa gene function for survival or tumor formation, they nonetheless activate this critical gene.Together, the authors overcame significant technical challenges to gain new insights into the different cells contributing to melanoma, underscoring the power of zebrafish as a model to uncover basic disease mechanisms. The results underline the plasticity of individual melanoma cells and the importance of targeting molecular processes in persister cells to efficiently counter melanoma relapse. The authors' techniques enable a deeper molecular characterization of melanoma tumors, opening the path for comparative studies with human melanoma with the aim of discovering new therapeutic targets.