Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression
Irina Primac, … , Donald Gullberg, Agnès Noel
Irina Primac, … , Donald Gullberg, Agnès Noel
Published July 9, 2019
Citation Information: J Clin Invest. 2019;129(11):4609-4628. https://doi.org/10.1172/JCI125890.
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Research Article Cell biology Oncology

Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression

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.

Authors

Irina Primac, Erik Maquoi, Silvia Blacher, Ritva Heljasvaara, Jan Van Deun, Hilde Y.H. Smeland, Annalisa Canale, Thomas Louis, Linda Stuhr, Nor Eddine Sounni, Didier Cataldo, Taina Pihlajaniemi, Christel Pequeux, Olivier De Wever, Donald Gullberg, Agnès Noel

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Figure 7

Integrin α11–expressing CAFs promote in vitro tumor cell invasion in response to PDGF-BB.

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Integrin α11–expressing CAFs promote in vitro tumor cell invasion in res...
(A–C) Representative spheroid pictures of red-tracked WT and KO mCAFs (A), CTRL and KD mCAFs (B), and CTRL and KD hCAF1 (C) after 20 hours of invasion in a 3D collagen matrix stimulated with PDGF-BB (10 ng/mL). Scale bars: 200 μm. Zoomed pictures (×2) are in lower right panels. Cell invasion quantification is presented in bottom panels. Data are expressed as maximal distance of invasion from the spheroid border (Lmax). n = 5–20 (A); n = 5–8 (B); n = 6–15 (C). Representative of 3 independent experiments. One-way ANOVA with Tukey’s multiple-comparisons test. (D–F) Representative homo- and heterospheroid pictures of green-tracked PyMT tumor cells and red-tracked WT and KO mCAFs (D) and green-tracked MCF-7 and MDA-MB-231 tumor cells and red-tracked CTRL and KD hCAF1 (E and F) after 20 hours of seeding in collagen. Scale bars: 200 μm. Zoomed pictures (×2) in lower right panels. Bottom panels correspond to tumor cell invasion quantification (Lmax). n = 5–18 (D); n = 8–19 (E); n = 5–13 (F). Representative of 3 independent experiments. One-way ANOVA with Tukey’s multiple-comparisons test.