University of Oulu

J Clin Invest. 2019;129(11):4609-4628. https://doi.org/10.1172/JCI125890

Stromal integrin alpha 11 regulates PDGFRβ signaling and promotes breast cancer progression

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Author: Primac, Irina1; Maquoi, Erik1; Blacher, Silvia1;
Organizations: 1Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium
2Oulu Centre for Cell–Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Department of Biomedicine and Centre for Cancer Biomarkers (CCBIO), Norwegian Centre of Excellence, University of Bergen, Bergen, Norway
4Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 26.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202002216096
Language: English
Published: American Society for Clinical Investigation, 2019
Publish Date: 2020-02-21
Description:

Abstract

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors, such as breast cancer (BC). Herein, we identify an integrin α11/PDGFRβ–positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin α11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin α11 and PDGFRβ was found at both transcriptional and histological levels in BC specimens. High stromal integrin α11/PDGFRβ expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using 5 CAF subpopulations (1 murine, 4 human) revealed that integrin α11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin α11 relies on its ability to interact with PDGFRβ in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a proinvasive matricellular protein. Pharmacological inhibition of PDGFRβ and JNK impaired tumor cell invasion induced by integrin α11+ CAFs. Collectively, our study uncovers an integrin α11+ subset of protumoral CAFs that exploits the PDGFRβ/JNK signaling axis to promote tumor invasiveness in BC.

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Series: Journal of clinical investigation
ISSN: 0021-9738
ISSN-E: 1558-8238
ISSN-L: 0021-9738
Volume: 129
Issue: 11
Pages: 4509 - 4528
DOI: 10.1172/JCI125890
OADOI: https://oadoi.org/10.1172/JCI125890
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
1182 Biochemistry, cell and molecular biology
Subjects:
Funding: We thank all laboratory members for useful technical advice, and all members of Marie Curie CAFFEIN Innovative Training Network (ITN) for valuable scientific discussions. We thank GIGA Imaging and Animal Facility platforms of ULiège for technical support and mouse housing. We thank the Biobank of ULiège for providing BC samples. This project was part of the CAFFEIN FP7 ITN consortium and received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program FP7/2007-2013/ under Research Executive Agency grant agreement 316610. The opinions presented in this article reflect only the authors’ views, and the European Union is not liable for any use that may be made of the information contained herein. This work was supported by grants from the Fonds de la Recherche Scientifique (FRS-FNRS, Belgium), the Fondation contre le Cancer (Foundation of Public Interest, Belgium), the Fonds Spéciaux de la Recherche (University of Liège), the Fondation Hospital-Universitaire Léon Frédéricq (University of Liège), the Research Council of Norway through its Centres of Excellence funding scheme (project 223250), the Academy of Finland Research Council for Health (grant 308867), and the Sigrid Jusélius Foundation, IUAP Belspo. AC and TL are supported by FNRS-Televie fellowships. EM is a Research Associate from FNRS (Belgium).
Copyright information: © 2019, American Society for Clinical Investigation.