Stromal Integrin α11 Regulates PDGFRβ Signaling to Promote Breast Cancer Progression

Introduction: Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors, such as breast cancer (BC) where the stroma represents up to 90 % of the tumor mass. Due to the heterogeneous feature of CAFs, there is no absolute molecular marker defining those fibroblastic cells. Identifying molecular determinants of functionally distinct CAF subsets is therefore critical to elucidate the contrasting biological actions of these stromal cells. Recently, integrin α11 (ITGA11) emerged as a novel biomarker of CAFs. Prompted by findings of prominent expression of this integrin in human BCs, we set out to identify the subset of CAFs expressing integrin α11, to investigate its contribution in BC growth and invasion in vitro and in vivo, and to molecularly define its role in CAFs.

Material and methods: For this study, we applied in vivo, in silico and in vitro approaches. In vivo, we genetically induced the ITGA11 ablation in the MMTV-PyMT mouse model of invasive BC and analysed tumor growth and metastasis. In silico tools were used to study integrin α11 role in human BC and its correlation with various stromal markers. BC mouse and patient-derived histological samples were also analysed for co-localisation studies. For mechanistic investigations, we used mouse and human isolated CAFs in in vitro functional and molecular assays.

Results and discussion: Herein, we demonstrate that integrin α11 identifies a specific PDGFRβ+ subset of fibroblasts with tumor-promoting characteristics in BC. Increased ITGA11 expression observed in human BC stroma was associated with poor survival and higher metastatic rate. These data were supported by preclinical studies in the MMTV-PyMT mouse model where integrin α11 expression was correlated with tumor progression and metastasis. Significant α11-PDGFRβ genetic and histological association was observed in human and mouse breast carcinomas. Proliferative and pro-invasive features of stromal α11 integrin were supported by its in vivo genetic ablation in the PyMT model and in vitro deletion in isolated breast-derived CAFs. Co-immunoprecipitation studies in CAFs revealed that integrin α11 forms a molecular complex with PDGFRβ in a ligand-dependent manner. Mechanistically, we uncovered a novel functional role of CAF-derived integrin α11 in regulating PDGFRβ signaling pathway and promoting Src, Crk and JNK downstream activation.

Conclusion: This study illustrates the molecular partnership between integrin α11 and PDGFRβ in a specific subset of CAFs displaying tumor-promoting and pro-metastatic features in BC.