Cancer associated fibroblast-derived integrin α11 regulates PDGFRβ signaling to promote breast cancer progression

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by mesenchymal cells and is correlated with fibroblast activation and matrix reorganization. While the role of ITGA11 in wound healing has been well described, only a very limited number of reports have assessed its role in the cancer disease.
This research project aims to investigate the role of stromal ITGA11 in breast cancer. To analyze the in vivo effects of ITGA11 on tumor insurgence, growth and metastasis, we crossed the oncogenic MMTv-PyMT mice with the ITGA11 KO/WT mice, which develop spontaneously breast tumors. ITGA11 deletion strongly delayed tumor growth and metastasis in PyMT mouse model. ITGA11 was poorly expressed at early stages of the tumor progression and its expression was strongly increased in the late stage invasive carcinomas. Importantly, a reduced angiogenesis and collagen content was observed in tumors lacking of ITGA11. Furthermore, a strong co-localization between ITGA11 and PDGFRb, but not other CAF markers such as alpha smooth actin, was also observed within the tumor stroma, suggesting that ITGA11 defines a subpopulation of CAFs, which is not represented by myofibroblasts, but rather PDGFRb+ CAFs.
For mechanistic investigation, CAFs and breast cancer cells were isolated from the PyMT model. ITGA11 co-immunoprecipitated with PDGFRb in the isolated CAFs and regulated its phosphorylation. Interestingly, ITGA11-deficient CAFs failed to promote CAF and cancer cell invasion, in contrast to WT CAFs in a spheroid invasion assay. A high throughput comparative proteomics analysis on CAF spheroids in 3D a system was next performed. Proteomics data identified several proteins with relevance in the cancer disease which were significantly modulated in CAFs through ITGA11 down-regulation. The top-ranking candidates are under validation and molecular pathways, which may link these targets and ITGA11 will be further analyzed in the in vitro models.
Overall, these in vivo and in vitro data show that ITGA11 defines a PDGFRβ+ subpopulation of CAFs distinct from α-SMA+ myofibroblasts that promote tumor cell invasion and angiogenesis at late stages of carcinoma evolution. ITGA11 is a promising target within the stroma of breast cancer and further investigations of its molecular signaling pathways will be of great relevance.