Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms.

Adult Aged Aged, 80 and over Axilla Breast Neoplasms / mortality Cancer-Associated Fibroblasts / metabolism Cell Proliferation Cell Separation Chemokine CXCL12 / metabolism Epithelial-Mesenchymal Transition Female Flow Cytometry Follow-Up Studies Humans Kaplan-Meier Estimate Lymph Nodes / cytology Lymphatic Metastasis / pathology Middle Aged Myofibroblasts / metabolism Neoplasm Invasiveness / pathology Primary Cell Culture Prognosis Progression-Free Survival Receptors, Notch / metabolism Signal Transduction Transforming Growth Factor beta / metabolism Tumor Cells, Cultured Tumor Microenvironment

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
21 01 2020
Historique:
received: 13 02 2019
accepted: 17 12 2019
entrez: 23 1 2020
pubmed: 23 1 2020
medline: 12 5 2020
Statut: epublish

Résumé

Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

Identifiants

DOI: 10.1038/s41467-019-14134-w PMID: 31964880 PMC: PMC6972713
pubmed: 31964880
doi: 10.1038/s41467-019-14134-w
pii: 10.1038/s41467-019-14134-w
pmc: PMC6972713
doi:

Substances chimiques

CXCL12 protein, human 0
Chemokine CXCL12 0
Receptors, Notch 0
Transforming Growth Factor beta 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Video-Audio Media

Langues

eng

Sous-ensembles de citation

IM

Pagination

404

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Auteurs

Floriane Pelon (F)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-2611-7728

Brigitte Bourachot (B)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0001-7816-0539

Yann Kieffer (Y)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-2722-3071

Ilaria Magagna (I)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-4092-5457

Fanny Mermet-Meillon (F)

Analysis of Transduction Pathway, Institut Curie, Inserm, U830, PSL Research University, 26 rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0002-5114-2354

Isabelle Bonnet (I)

Institut Curie, Biology-inspired Physics at MesoScales Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, CNRS UMR168, PSL Research University, Sorbonne Université, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-2343-3784

Ana Costa (A)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0002-0893-3388

Anne-Marie Givel (AM)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.

Youmna Attieh (Y)

Institut Curie, Cell Migration and Invasion, UMR144, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-1110-4991

Jorge Barbazan (J)

Institut Curie, Cell Migration and Invasion, UMR144, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0002-7165-8497

Claire Bonneau (C)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0001-6251-286X

Laetitia Fuhrmann (L)

Department of Pathology, Institut Curie Hospital, 26, rue d'Ulm, F-75248, Paris, France.
ORCID: 0000-0003-1755-6307

Stéphanie Descroix (S)

Institut Curie, Laboratoire Physico Chimie Curie, Institut Pierre-Gilles de Gennes, CNRS UMR168, 75005, Paris, France.
ORCID: 0000-0003-0027-352X

Danijela Vignjevic (D)

Institut Curie, Cell Migration and Invasion, UMR144, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0003-4250-703X

Pascal Silberzan (P)

Institut Curie, Biology-inspired Physics at MesoScales Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, CNRS UMR168, PSL Research University, Sorbonne Université, 26, rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0002-8554-882X

Maria Carla Parrini (MC)

Analysis of Transduction Pathway, Institut Curie, Inserm, U830, PSL Research University, 26 rue d'Ulm, F-75005, Paris, France.
ORCID: 0000-0002-7082-9792

Anne Vincent-Salomon (A)

Department of Pathology, Institut Curie Hospital, 26, rue d'Ulm, F-75248, Paris, France.

Fatima Mechta-Grigoriou (F)

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France. fatima.mechta-grigoriou@curie.fr.
Inserm, U830, 26, rue d'Ulm, F-75005, Paris, France. fatima.mechta-grigoriou@curie.fr.
ORCID: 0000-0002-3751-6989

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questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Chimiokines › Chimiokines CXC › Chimiokine CXCL12 › Cancer-associated fibroblast heterogeneity in...
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