Stromal integrin α11 regulates PDGFR-β signaling and promotes breast cancer progression
PRIMAC, I; MAQUOI, E; BLACHER, S; HELJASVAARA, R; Van Deun, Jan; Smeland, Hilde Ytre-Hauge; CANALE, A; LOUIS, T; Stuhr, Linda Elin Birkhaug; SOUNNI, NE; CATALDO, D; PIHLAJANEMI, T; PEQUEUX, C; DE WEAVER, O; Gullberg, Donald; Noel, Agnes
Peer reviewed, Journal article
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Date
2019Metadata
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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.