Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity

• Published in: Cell reports (Cambridge) 2016-09, Vol.17 (1), p.233-248
• Main Authors: Sangaletti, Sabina, Tripodo, Claudio, Santangelo, Alessandra, Castioni, Nadia, Portararo, Paola, Gulino, Alessandro, Botti, Laura, Parenza, Mariella, Cappetti, Barbara, Orlandi, Rosaria, Tagliabue, Elda, Chiodoni, Claudia, Colombo, Mario P.
• Format: Article
• Language: English
• Subjects: aminobisphosphonates; Animals; Antigen Presentation; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Celecoxib - pharmacology; Cell Line, Tumor; COX-2; CXCL12; cyclooxygenase-2; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; ECM; EMT; epithelial to mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - immunology; extracellular matrix; Extracellular Matrix - immunology; Extracellular Matrix - pathology; Female; G-CSF; Gene Expression; GM-CSF; granulocyte colony-stimulating factor; granulocyte-macrophage colony-stimulating factor; Humans; Mast Cells - drug effects; Mast Cells - immunology; Mast Cells - pathology; MDSC; Mice; Mice, Inbred BALB C; Mice, Knockout; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - pathology; myeloid-derived suppressor cells; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - pathology; Neoplasm Grading; Osteonectin - deficiency; Osteonectin - genetics; Polyethylene Glycols - pharmacology; SPARC; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Xenograft Model Antitumor Assays
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.08.075

The extracellular matrix (ECM) contributes to the biological and clinical heterogeneity of breast cancer, and different prognostic groups can be identified according to specific ECM signatures. In high-grade, but not low-grade, tumors, an ECM signature characterized by high SPARC expression (ECM3) identifies tumors with increased epithelial-to-mesenchymal transition (EMT), reduced treatment response, and poor prognosis. To better understand how this ECM3 signature is contributing to tumorigenesis, we expressed SPARC in isogenic cell lines and found that SPARC overexpression in tumor cells reduces their growth rate and induces EMT. SPARC expression also results in the formation of a highly immunosuppressive microenvironment, composed by infiltrating T regulatory cells, mast cells, and myeloid-derived suppressor cells (MDSCs). The ability of SPARC to induce EMT depended on the localization and suppressive function of myeloid cells, and inhibition of the suppressive function MDSCs by administration of aminobisphosphonates could revert EMT, rendering SPARC-overexpressing tumor cells sensitive to Doxil. We conclude that that SPARC is regulating the interplay between MDSCs and the ECM to drive the induction of EMT in tumor cells. [Display omitted] •In breast cancer, the extracellular matrix can impact the immune microenvironment•Suppressive activity of myeloid cells is required for EMT of breast cancer cells•Interrupting ECM-MDSCs crosstalk can revert EMT and restore chemosensitivity Sangaletti et al. show that in high-grade breast cancer, the mesenchymal transition depends on extracellular matrix (ECM)-mediated control of myeloid-derived suppressor cell (MDSC) activity. Interrupting this ECM-MDSC crosstalk with aminobisphosphonates can revert the EMT to restore chemosensitivity.