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A cellular hierarchy in melanoma uncouples growth and metastasis

Author

Listed:
  • Panagiotis Karras

    (VIB
    KU Leuven)

  • Ignacio Bordeu

    (University of Cambridge
    The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge
    Universidad de Chile)

  • Joanna Pozniak

    (VIB
    KU Leuven)

  • Ada Nowosad

    (VIB
    KU Leuven)

  • Cecilia Pazzi

    (VIB
    KU Leuven)

  • Nina Raemdonck

    (VIB
    KU Leuven)

  • Ewout Landeloos

    (VIB
    KU Leuven)

  • Yannick Herck

    (UZ Leuven)

  • Dennis Pedri

    (VIB
    KU Leuven)

  • Greet Bervoets

    (VIB
    KU Leuven)

  • Samira Makhzami

    (VIB
    KU Leuven)

  • Jia Hui Khoo

    (BGI-Shenzhen)

  • Benjamin Pavie

    (VIB Center for Brain and Disease Research
    VIB Center for Inflammation Research
    Ghent University)

  • Jochen Lamote

    (VIB)

  • Oskar Marin-Bejar

    (VIB
    KU Leuven)

  • Michael Dewaele

    (VIB
    KU Leuven)

  • Han Liang

    (BGI-Shenzhen)

  • Xingju Zhang

    (BGI-Shenzhen)

  • Yichao Hua

    (KU Leuven
    VIB)

  • Jasper Wouters

    (VIB-KU Leuven
    KU Leuven)

  • Robin Browaeys

    (VIB Center for Inflammation Research
    Ghent University)

  • Gabriele Bergers

    (KU Leuven
    VIB)

  • Yvan Saeys

    (VIB Center for Inflammation Research
    Ghent University)

  • Francesca Bosisio

    (KU Leuven)

  • Joost Oord

    (KU Leuven)

  • Diether Lambrechts

    (VIB
    KU Leuven)

  • 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
    The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge
    University of Cambridge)

  • Florian Rambow

    (VIB
    KU Leuven
    Institute for AI in Medicine (IKIM), University Hospital Essen
    University Duisburg-Essen)

  • Jean-Christophe Marine

    (VIB
    KU Leuven)

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.

Suggested Citation

  • 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 & , 2022. "A cellular hierarchy in melanoma uncouples growth and metastasis," Nature, Nature, vol. 610(7930), pages 190-198, October.
  • Handle: RePEc:nat:nature:v:610:y:2022:i:7930:d:10.1038_s41586-022-05242-7
    DOI: 10.1038/s41586-022-05242-7
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    Citations

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    Cited by:

    1. Guillaume Harmange & Raúl A. Reyes Hueros & Dylan L. Schaff & Benjamin Emert & Michael Saint-Antoine & Laura C. Kim & Zijian Niu & Shivani Nellore & Mitchell E. Fane & Gretchen M. Alicea & Ashani T. W, 2023. "Disrupting cellular memory to overcome drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Michael F. Emmons & Richard L. Bennett & Alberto Riva & Kanchan Gupta & Larissa Anastasio Da Costa Carvalho & Chao Zhang & Robert Macaulay & Daphne Dupéré-Richér & Bin Fang & Edward Seto & John M. Koo, 2023. "HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. F. Nadalin & M. J. Marzi & M. Pirra Piscazzi & P. Fuentes-Bravo & S. Procaccia & M. Climent & P. Bonetti & C. Rubolino & B. Giuliani & I. Papatheodorou & J. C. Marioni & F. Nicassio, 2024. "Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    4. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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