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 Article has an altmetric score of 15

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 6

Integrin α11/PDGFRβ density is associated with a poor clinical outcome in BC.

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Integrin α11/PDGFRβ density is associated with a poor clinical outcome i...
(A) Representative confocal pictures of immunofluorescence costaining of integrin α11 (red) and PDGFRβ (green) in human breast samples: tumor tissues and normal associated tissues from patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of luminal A and B, HER2, or triple-negative (TNBC) breast cancers. Scale bar: 50 μm. Nuclei stained with DAPI (blue). (B–D) Quantification of density of integrin α11 (B), PDGFRβ (C), and their colocalization (D) on BC samples. Data are presented as percentage of stained area normalized to total tumor area. n = 68 patients (n = 11 DCIS, n = 14 IDC luminal A, n = 17 IDC luminal B, n = 11 IDC HER2, n = 15 IDC TNBC). One-way ANOVA with Dunnett’s (B) and Kruskal-Wallis with Dunn’s multiple-comparisons tests (C and D). (E and F) Overall percentage of integrin α11/PDGFRβ–positive cells normalized to total integrin α11+ (E) or PDGFRβ+ cells (F). Minimum 6 stromal fields per tumor, n = 68 patients. Kruskal-Wallis with Dunn’s multiple-comparisons test. (G) Correlation of integrin α11/PDGFRβ colocalization density from D with percentage of Ki67 in human BC. n = 68 patients. Pearson correlation analysis. (H–J) Association of integrin α11/PDGFRβ colocalization density with BC grade (H), metastasis (I), and survival (J) outcomes. n = 68 patients. One-way ANOVA with Tukey’s multiple-comparisons (J) and Mann-Whitney (H and I) tests. (K) Quantification of spatial enrichment of integrin α11 (red), PDGFRβ (green), and colocalization (yellow) areas versus tumor areas in human BC samples. Data are presented as frequency of stained pixels as a function of the distance to tumor areas. n = 56 stromal fields. Significance between the distribution curves was determined by Kolmogorov-Smirnov test within the distance range of 0–100 μm.