Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity.
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.
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy. Electronic address: sabina.sangaletti@istitutotumori.mi.it.
Sabina
S
Sangaletti
Tumor Immunology Unit, Human Pathology Section, Department of Health Science, Palermo University School of Medicine, 90129 Palermo, Italy.
Claudio
C
Tripodo
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Alessandra
A
Santangelo
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Nadia
N
Castioni
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Paola
P
Portararo
Tumor Immunology Unit, Human Pathology Section, Department of Health Science, Palermo University School of Medicine, 90129 Palermo, Italy.
Alessandro
A
Gulino
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Laura
L
Botti
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Mariella
M
Parenza
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Barbara
B
Cappetti
Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Rosaria
R
Orlandi
Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Elda
E
Tagliabue
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Claudia
C
Chiodoni
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy. Electronic address: mariopaolo.colombo@istitutotumori.mi.it.
Mario P
MP
Colombo
D000818:Animals; D017951:Antigen Presentation; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000068579:Celecoxib / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000276:immunology*; D005109:Extracellular Matrix / Q000276:immunology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D060787:Neoplasm Grading; D015676:Osteonectin / Q000172:deficiency / Q000235:genetics*; D011092:Polyethylene Glycols / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015676:Osteonectin; C578250:SPARC protein, mouse; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000068579:Celecoxib
Breast cancer; COX-2; CXCL12; ECM; EMT; G-CSF; GM-CSF; MDSC; SPARC; aminobisphosphonates; cyclooxygenase-2; epithelial to mesenchymal transition; extracellular matrix; granulocyte colony-stimulating factor; granulocyte-macrophage colony-stimulating factor; myeloid-derived suppressor cells