Stromal integrin alpha 11 regulates PDGFRβ signaling and promotes breast cancer progression
Primac, Irina; Maquoi, Erik; Blacher, Silvia; Heljasvaara, Ritva; Van Deun, Jan; Smeland, Hilde Y.H.; Canale, Annalisa; Louis, Thomas; Stuhr, Linda; Sounni, Nor Eddine; Cataldo, Didier; Pihlajaniemi, Taina; Pequeux, Christel; De Wever, Olivier; Gullberg, Donald; Noel, Agnès (2019-07-09)
J Clin Invest. 2019;129(11):4609-4628. https://doi.org/10.1172/JCI125890
© 2019, American Society for Clinical Investigation.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe202002216096
Tiivistelmä
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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