期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 11, 页码 4509-4528出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI125890
关键词
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资金
- European Union [316610]
- Fonds de la Recherche Scientifique (FRS-FNRS, Belgium)
- Fondation contre le Cancer (Foundation of Public Interest, Belgium)
- Fonds Speciaux de la Recherche (University of Liege)
- Fondation Hospital-Universitaire Leon Fredericq (University of Liege)
- Research Council of Norway through its Centres of Excellence [223250]
- Academy of Finland Research Council for Health [308867]
- Sigrid Juselius Foundation
- FNRS-Televie fellowships
- FNRS (Belgium)
- IUAP Bels-po
- Academy of Finland (AKA) [308867, 308867] Funding Source: Academy of Finland (AKA)
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 alpha 11/PDGFR beta-positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha 11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha 11 and PDGFR beta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha 11/PDGFR beta 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 alpha 11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin alpha 11 relies on its ability to interact with PDGFR beta 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 PDGFR beta and JNK impaired tumor cell invasion induced by integrin alpha 11 CAFs. Collectively, our study uncovers an integrin alpha 11 subset of protumoral CAFs that exploits the PDGFR beta/JNK signaling axis to promote tumor invasiveness in BC.
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