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

Sabina Sangaletti, Claudio Tripodo, Alessandra Santangelo, Nadia Castioni, Paola Portararo, Alessandro Gulino, Laura Botti, Mariella Parenza, Barbara Cappetti, Rosaria Orlandi, Elda Tagliabue, Claudia Chiodoni, Mario P. Colombo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)233-248
Number of pages16
JournalCell Reports
Volume17
Issue number1
DOIs
Publication statusPublished - Sep 27 2016

Keywords

  • aminobisphosphonates
  • Breast cancer
  • COX-2
  • CXCL12
  • cyclooxygenase-2
  • ECM
  • EMT
  • epithelial to mesenchymal transition
  • extracellular matrix
  • G-CSF
  • GM-CSF
  • granulocyte colony-stimulating factor
  • granulocyte-macrophage colony-stimulating factor
  • MDSC
  • myeloid-derived suppressor cells
  • SPARC

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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