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A cellular hierarchy in melanoma uncouples growth and metastasis
Indexado
WoS WOS:000858380500001
Scopus SCOPUS_ID:85138498497
DOI 10.1038/S41586-022-05242-7
Año 2022
Tipo artículo de investigación

Citas Totales

Autores Afiliación Chile

Instituciones Chile

% Participación
Internacional

Autores
Afiliación Extranjera

Instituciones
Extranjeras


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.

Revista



Revista ISSN
Nature 0028-0836

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Disciplinas de Investigación



WOS
Multidisciplinary Sciences
Scopus
Sin Disciplinas
SciELO
Sin Disciplinas

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Publicaciones WoS (Ediciones: ISSHP, ISTP, AHCI, SSCI, SCI), Scopus, SciELO Chile.

Colaboración Institucional



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Autores - Afiliación



Ord. Autor Género Institución - País
1 Karras, Panagiotis Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
2 Bordeu, Ignacio Hombre Faculty of Mathematics - Reino Unido
Wellcome Trust/ Cancer Research UK Gurdon Institute - Reino Unido
Universidad de Chile - Chile
University of Cambridge - Reino Unido
UNIV CAMBRIDGE - Reino Unido
3 Pozniak, Joanna Mujer Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
4 Nowosad, Ada - Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
5 Pazzi, Cecilia Mujer Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
6 Van Raemdonck, Nina Mujer Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
7 Landeloos, Ewout Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
8 Van Herck, Yannick Hombre KU Leuven– University Hospital Leuven - Bélgica
KU Leuven - Bélgica
UZ Leuven - Bélgica
9 Pedri, Dennis Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
10 Bervoets, Greet Mujer Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
11 Makhzami, Samira Mujer Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
12 Khoo, Jia Hui - BGI-Shenzhen - China
BGI Shenzhen - China
13 Pavie, Benjamin Hombre Vlaams Instituut voor Biotechnologie - Bélgica
Universiteit Gent - Bélgica
VIB Ctr Brain & Dis Res - Bélgica
VIB Ctr Inflammat Res - Bélgica
Univ Ghent - Bélgica
14 Lamote, Jochen Hombre Vlaams Instituut voor Biotechnologie - Bélgica
VIB - Bélgica
15 Marin-Bejar, Oskar Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
16 Dewaele, Michael Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
17 Liang, Han - BGI-Shenzhen - China
BGI Shenzhen - China
18 Zhang, Xingju - BGI-Shenzhen - China
BGI Shenzhen - China
19 Hua, Yichao - KU Leuven - Bélgica
Vlaams Instituut voor Biotechnologie - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
20 Wouters, Jasper Hombre KU Leuven - Bélgica
VIB KU Leuven - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
21 Browaeys, Robin Hombre Vlaams Instituut voor Biotechnologie - Bélgica
Universiteit Gent - Bélgica
VIB Ctr Inflammat Res - Bélgica
Univ Ghent - Bélgica
22 Bergers, Gabriele Mujer KU Leuven - Bélgica
Vlaams Instituut voor Biotechnologie - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica
23 Saeys, Yvan Hombre Vlaams Instituut voor Biotechnologie - Bélgica
Universiteit Gent - Bélgica
VIB Ctr Inflammat Res - Bélgica
Univ Ghent - Bélgica
24 Bosisio, Francesca Mujer Departement Beeldvorming & Pathologie - Bélgica
KU Leuven - Bélgica
Katholieke Univ Leuven - Bélgica
25 van den Oord, Joost Hombre Departement Beeldvorming & Pathologie - Bélgica
KU Leuven - Bélgica
Katholieke Univ Leuven - Bélgica
26 Lambrechts, Diether Hombre Vlaams Instituut voor Biotechnologie - Bélgica
Departement Oncologie - Bélgica
VIB - Bélgica
KU Leuven - Bélgica
Katholieke Univ Leuven - Bélgica
27 Rustgi, Anil K. Hombre Columbia University Irving Medical Center - Estados Unidos
Columbia Univ - Estados Unidos
28 Bechter, Oliver Hombre KU Leuven– University Hospital Leuven - Bélgica
KU Leuven - Bélgica
UZ Leuven - Bélgica
29 Blanpain, Cedric Hombre Université libre de Bruxelles - Bélgica
Univ Libre Bruxelles ULB - Bélgica
30 Simons, Benjamin D. Hombre Faculty of Mathematics - Reino Unido
Wellcome Trust/ Cancer Research UK Gurdon Institute - Reino Unido
University of Cambridge - Reino Unido
UNIV CAMBRIDGE - Reino Unido
31 Rambow, Florian Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
Universitätsklinikum Essen - Alemania
Universität Duisburg-Essen - Alemania
partner site Essen - Alemania
VIB - Bélgica
German Canc Consortium DKTK - Alemania
Katholieke Univ Leuven - Bélgica
Univ Hosp Essen - Alemania
Univ Duisburg Essen - Alemania
UZ Leuven - Bélgica
German Cancer Research Center - Alemania
32 Marine, Jean Christophe Hombre Vlaams Instituut voor Biotechnologie - Bélgica
KU Leuven - Bélgica
VIB - Bélgica
Katholieke Univ Leuven - Bélgica
UZ Leuven - Bélgica

Muestra la afiliación y género (detectado) para los co-autores de la publicación.

Financiamiento



Fuente
EPSRC
Wellcome Trust
Alexander von Humboldt Foundation
Royal Society
Engineering and Physical Sciences Research Council
FWO
Stichting tegen Kanker
Fonds Wetenschappelijk Onderzoek
Alexander von Humboldt-Stiftung
Marie Curie
KU Leuven
Vlaams Instituut voor Biotechnologie
Research Foundation-Flanders (FWO)
Melanoma Research Alliance
Flemish Government, department EWI
Boehringer Ingelheim Fonds
Vlaams Supercomputer Centrum
Neftkens foundation
European Orthodontic Society
Belgian Excellence of Science
Royal Society E. P. Abraham Research Professorship
Marie Curie Individual Fellowship (H2020-MSCA-IF-2018)
KU Leuven (C1 grant)
VIB PhD international programme
Marie Curie Individual Fellowship (H2020-MSCA-IF-2019)
Stichting tegen Kanker (Foundation against Cancer)
FWO at the program under the Marie Sklodowska-Curie grant
FWO-SB
Belgian Excellence of Science (EOS) programme

Muestra la fuente de financiamiento declarada en la publicación.

Agradecimientos



Agradecimiento
We thank G. Ghanem for providing us with the MM lines; H. Clevers for providing us with the Confetti-reporter mouse strain; and O. Van Goethem and V. Benne for their assistance with the mouse experiments; the members of the VIB Technology Watch members, M. Bontinck and Y.-C. Wang, for facilitating collaborations with Resolve Biosciences and BGI research, respectively; and Y. Oren and the laboratories of A. Regev and J. Brugge for providing the watermelon vector. P.K. received financial support from an Marie Curie Individual Fellowship (H2020‐MSCA‐IF‐2018, 841092), FWO (1210520N) and Stichting tegen Kanker (Foundation against Cancer, 2021-028). J.P. received financial support from a Marie Curie Individual Fellowship (H2020‐MSCA‐IF‐2019, 896897). A.N. received postdoctoral from the KU Leuven (PDMT1/21/035). C.P. received PhD research fellowships from FWO (11M3822N) and of the Boehringer Ingelheim Fonds. J.W. received a postdoctoral research fellowship from Stichting Tegen Kanker (Foundation against Cancer; 2019-100). O.M.-B. was supported by the 12T1217N project by the FWO at the program under the Marie Skłodowska-Curie grant agreement no. 665501. D.P. and N.V.D. received PhD fellowships from the VIB PhD international programme and FWO-SB 1S79619N, respectively. F.R. acknowledges support from the Alexander von Humboldt Foundation. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Centre), funded by the Research Foundation–Flanders (FWO) and the Flemish Government, department EWI. B.D.S. acknowledges funding from the Royal Society E. P. Abraham Research Professorship (RP\R1\180165), EPSRC (EP/P034616/1) and Wellcome Trust (219478/Z/19/Z). This work was supported by the FWO (G0C530N and G070622N), Stichting Tegen Kanker (FAF-F/2018/1265), Neftkens foundation, Melanoma Research Alliance (MRA, EIA#623591), KU Leuven (C1 grant) and the Belgian Excellence of Science (EOS) programme to J.-C.M.
We thank G. Ghanem for providing us with the MM lines; H. Clevers for providing us with the Confetti-reporter mouse strain; and O. Van Goethem and V. Benne for their assistance with the mouse experiments; the members of the VIB Technology Watch members, M. Bontinck and Y.-C. Wang, for facilitating collaborations with Resolve Biosciences and BGI research, respectively; and Y. Oren and the laboratories of A. Regev and J. Brugge for providing the watermelon vector. P.K. received financial support from an Marie Curie Individual Fellowship (H2020‐MSCA‐IF‐2018, 841092), FWO (1210520N) and Stichting tegen Kanker (Foundation against Cancer, 2021-028). J.P. received financial support from a Marie Curie Individual Fellowship (H2020‐MSCA‐IF‐2019, 896897). A.N. received postdoctoral from the KU Leuven (PDMT1/21/035). C.P. received PhD research fellowships from FWO (11M3822N) and of the Boehringer Ingelheim Fonds. J.W. received a postdoctoral research fellowship from Stichting Tegen Kanker (Foundation against Cancer; 2019-100). O.M.-B. was supported by the 12T1217N project by the FWO at the program under the Marie Skłodowska-Curie grant agreement no. 665501. D.P. and N.V.D. received PhD fellowships from the VIB PhD international programme and FWO-SB 1S79619N, respectively. F.R. acknowledges support from the Alexander von Humboldt Foundation. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Centre), funded by the Research Foundation–Flanders (FWO) and the Flemish Government, department EWI. B.D.S. acknowledges funding from the Royal Society E. P. Abraham Research Professorship (RP\R1\180165), EPSRC (EP/P034616/1) and Wellcome Trust (219478/Z/19/Z). This work was supported by the FWO (G0C530N and G070622N), Stichting Tegen Kanker (FAF-F/2018/1265), Neftkens foundation, Melanoma Research Alliance (MRA, EIA#623591), KU Leuven (C1 grant) and the Belgian Excellence of Science (EOS) programme to J.-C.M.
We thank G. Ghanem for providing us with the MM lines; H. Clevers for providing us with the Confetti-reporter mouse strain; and O. Van Goethem and V. Benne for their assistance with the mouse experiments; the members of the VIB Technology Watch members, M. Bontinck and Y.-C. Wang, for facilitating collaborations with Resolve Biosciences and BGI research, respectively; and Y. Oren and the laboratories of A. Regev and J. Brugge for providing the watermelon vector. P.K. received financial support from an Marie Curie Individual Fellowship (H2020-MSCA-IF-2018, 841092), FWO (1210520N) and Stichting tegen Kanker (Foundation against Cancer, 2021-028). J.P. received financial support from a Marie Curie Individual Fellowship (H2020-MSCA-IF-2019, 896897). A.N. received postdoctoral from the KU Leuven (PDMT1/21/035). C.P. received PhD research fellowships from FWO (11M3822N) and of the Boehringer Ingelheim Fonds. J.W. received a postdoctoral research fellowship from Stichting Tegen Kanker (Foundation against Cancer; 2019-100). O.M.-B. was supported by the 12T1217N project by the FWO at the program under the Marie Sklodowska-Curie grant agreement no. 665501. D.P. and N.V.D. received PhD fellowships from the VIB PhD international programme and FWO-SB 1S79619N, respectively. F.R. acknowledges support from the Alexander von Humboldt Foundation. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Centre), funded by the Research Foundation-Flanders (FWO) and the Flemish Government, department EWI. B.D.S. acknowledges funding from the Royal Society E. P. Abraham Research Professorship (RP\R1\180165), EPSRC (EP/P034616/1) and Wellcome Trust (219478/Z/19/Z). This work was supported by the FWO (G0C530N and G070622N), Stichting Tegen Kanker (FAF-F/2018/1265), Neftkens foundation, Melanoma Research Alliance (MRA, EIA#623591), KU Leuven (C1 grant) and the Belgian Excellence of Science (EOS) programme to J.-C.M.

Muestra la fuente de financiamiento declarada en la publicación.