Original Article

Leukemia advance online publication 28 April 2017; doi: 10.1038/leu.2017.102

Proteomic characterization of human multiple myeloma bone marrow extracellular matrix

S V Glavey1,2,10, A Naba3,10,11, S Manier1,10, K Clauser4, S Tahri1, J Park1, M R Reagan1, M Moschetta1, Y Mishima1, M Gambella5, A Rocci6, A Sacco1,7, M E O'Dwyer2, J M Asara8, A Palumbo5, A M Roccaro1,7,12, R O Hynes3,9,12 and I M Ghobrial1,12

  1. 1Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  2. 2Department of Hematology, National University of Ireland, Galway, Ireland
  3. 3Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
  4. 4Protemics Platform, Broad Institute, Cambridge, MA, USA
  5. 5University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
  6. 6Manchester Royal Infirmary and Central Manchester University Hospital NHS Foundation, University of Manchester, Manchester, UK
  7. 7SST Spedali Civili, Department Medical Oncology, CREA Laboratory, Brescia, Italy
  8. 8Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  9. 9Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA

Correspondence: Professor RO Hynes, Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA E-mail: rohynes@mit.edu; Professor IM Ghobrial, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. E-mail: Irene_ghobrial@dfci.harvard.edu

10These authors contributed equally to this work.

11Current address: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA.

12Co-last authors.

Received 28 December 2016; Revised 4 March 2017; Accepted 8 March 2017
Accepted article preview online 27 March 2017; Advance online publication 28 April 2017

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Abstract

The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.