Studying melanoma evolution and therapy resistance one cell at the time

Chris Marine is Professor, senior VIB group leader and Director of the VIB/KULeuven center for Cancer Biology. 

Summury : Although melanoma is notorious for its high degree of heterogeneity and plasticity, the origin and magnitude of cell state diversity remains poorly understood. Equally, it is not known whether melanoma growth, metastatic dissemination and therapy resistance are supported by overlapping or distinct melanoma subpopulations. By combining mouse genetics, unbiased lineage tracing and quantitative modelling, single-cell and spatial transcriptomics, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying embryonic neural crest cell fate specification and differentiation. Our findings indicate that tumorigenic competence is associated with a spatially localized perivascular niche environment, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Moreover, temporal single-cell tracing of a population of melanoma cells harbouring a mesenchymal-like state revealed that these cells constitute a pool of metastatic-initiating cells. We also obtained evidence that the mesenchymal-like state is a driver of intrinsic resistance to immunotherapy and acquired resistance to targeted therapy.

Single-cell transcriptomics is the state-of-the-art method to assess cancer cell state diversity. Taking advantage of a new method we developed to monitor cell state diversity and plasticity in real time, we performed a proof-of-concept drug screen for compounds that decrease viability of these drug-resilient cells and thereby increase response to standard-of-care therapy in clinically relevant preclinical models. Our data provide a spatially and temporally resolved map of the diversity and trajectories of cancer cell states within the evolving melanoma ecosystem and suggest that the ability to support growth and metastasis and therapy resistance are limited to distinct pools of melanoma cells.

Chris Marine bio