Proteomic characterization of human multiple myeloma bone marrow extracellular matrix

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.

From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells

“…Similar to healthy PC, MM cells initially depend on signals from the BM microenvironment for their survival (4). Intricate interactions between MM cells and cells from the BM microenvironment play an important role in MM proliferation, survival, migration, and drug resistance (4,59). The nature and relevance of the microenvironment in MM have been described extensively elsewhere, including the important role of bone and immune cells in MM pathophysiology (60,61).…”

“…A proteomic analysis of fibroblast-like cells and ECM demonstrated that ECM proteins, ECM receptors, and ECM-modulating enzymes are progressively upregulated from MGUS to MM (59). Two proteins, Annexin A2 (ANXA2) and Galectin-2 (LGALS2), were identified in the BM ECM of MM but were absent in BM from healthy donors or MGUS patients (59).…”

“…A proteomic analysis of fibroblast-like cells and ECM demonstrated that ECM proteins, ECM receptors, and ECM-modulating enzymes are progressively upregulated from MGUS to MM (59). Two proteins, Annexin A2 (ANXA2) and Galectin-2 (LGALS2), were identified in the BM ECM of MM but were absent in BM from healthy donors or MGUS patients (59). Remarkably, high expression of these proteins was associated with decreased overall survival, suggesting that remodeling of BM ECM contributes to a permissive tumor microenvironment (59).…”

Hydrophilic cell-derived extracellular matrix as a niche to promote adhesion and differentiation of neural progenitor cells

“…7 It has been proved that ECM provides a mechanical support and signaling cues to regulate cell survival, proliferation, differentiation and metastasis via the interaction of cells and ECM. [8][9][10][11] Given the advantageous features, native tissue-derived ECM, mainly derived from allogeneic and xenogeneic tissues treated with chemical or thermal decellularization, has been utilized extensively toward promoting tissue engineering and regenerative medicine. 12 However, tissue-derived ECM has several limitations, such as limited donors, inammatory reactions, pathogens transfer disease and uncontrollable degradation.…”

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…We have recently shown that the BM extracellular matrix (ECM) and MSC compartments [42] are significantly different between MM patients’ and healthy donors’ BM [42,43]. These alterations in the host microenvironment ultimately support tumor growth, bone disease, and drug resistance (for example, through induction of MUC1 as recently demonstrated by Bar-Natan et al [44]), and it is very likely that MAT effects MSCs and the BM ECM.…”