A cellular hierarchy in melanoma uncouples growth and metastasis

Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Raemdonck, Ewout Landeloos, Yannick Herck, Dennis Pedri, Greet Bervoets, Samira Makhzami, Jia Hui Khoo, Benjamin Pavie, Jochen Lamote, Oskar Marin-Bejar, Michael Dewaele, Han Liang, Xingju Zhang, Yichao Hua, Jasper Wouters, Robin Browaeys, Gabriele Bergers, Yvan Saeys, Francesca Bosisio, Joost Oord, Diether Lambrechts, Anil K. Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin D. Simons, Florian Rambow () and Jean-Christophe Marine ()
Additional contact information
Panagiotis Karras: VIB
Ignacio Bordeu: University of Cambridge
Joanna Pozniak: VIB
Ada Nowosad: VIB
Cecilia Pazzi: VIB
Nina Raemdonck: VIB
Ewout Landeloos: VIB
Yannick Herck: UZ Leuven
Dennis Pedri: VIB
Greet Bervoets: VIB
Samira Makhzami: VIB
Jia Hui Khoo: BGI-Shenzhen
Benjamin Pavie: VIB Center for Brain and Disease Research
Jochen Lamote: VIB
Oskar Marin-Bejar: VIB
Michael Dewaele: VIB
Han Liang: BGI-Shenzhen
Xingju Zhang: BGI-Shenzhen
Yichao Hua: KU Leuven
Jasper Wouters: VIB-KU Leuven
Robin Browaeys: VIB Center for Inflammation Research
Gabriele Bergers: KU Leuven
Yvan Saeys: VIB Center for Inflammation Research
Francesca Bosisio: KU Leuven
Joost Oord: KU Leuven
Diether Lambrechts: VIB
Anil K. Rustgi: Columbia University Irving Medical Center
Oliver Bechter: UZ Leuven
Cedric Blanpain: Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB)
Benjamin D. Simons: University of Cambridge
Florian Rambow: VIB
Jean-Christophe Marine: VIB

Nature, 2022, vol. 610, issue 7930, 190-198

Abstract: Abstract Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.

Date: 2022
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DOI: 10.1038/s41586-022-05242-7

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