Mapping intratumoral heterogeneity and dynamics in melanoma progression and metastasis

Melanoma represents the most aggressive and the deadliest form of skin cancer with diverse socio-economical implications worldwide. Standard of care therapeutic approaches mainly include surgical resection, immunotherapy and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient’s characteristics and location of the tumor. However, the efficacy of these treatments against metastatic disease remains very poor and almost invariably transient due to the development of resistance. A key factor contributing to the lethal outcome of metastasis, therapeutic failure, and drug resistance is intratumoral heterogeneity, especially at the metastatic sites of the disease. This heterogeneity can result from genetic, transcriptomic, epigenetic, and/or phenotypic changes at primary and metastatic sites. We are extensively and continuously characterizing the transcriptomic and epi-(genomic) landscape of melanoma (that is richer than previously described) by combining in vivo lineage tracing of physiological models and unbiased high-throughput multi -omic technologies that allow the profiling of individual cells using next-generation sequencing. The identification of multiple melanoma cell states, strikingly and for the first time, revealed that these states are hierarchically organized and their spatially distribution leads to different phenotypic characteristics. To gain more insights of the intratumoral heterogeneity in melanoma progression and metastasis we aim to fully characterize the physiological relevance and the functional role of each state in vivo and in human biopsies at different stages of the disease. Importantly, we aim to map their spatial distribution and how the Tumor MicroEnvironment (TME) can shape the phenotypic diversity of each state.