Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

Abstract

Key Points• 3D bone marrow niche model recapitulates in vivo interactions of tumor and bone cells in a more biologically relevant system than in 2D.• Differential expression levels of miRs in MSCs provide novel insights into mechanisms of regulation of osteoblasts in multiple myeloma.Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required.Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillarylike assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)-and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation. (Blood. 2014;124(22):3250-3259)

3D tissue-engineered bone marrow as a novel model to study pathophysiology and drug resistance in multiple myeloma

“…Previous models have been developed to recreate the 3D microenvironment of the BM using collagen [15, 16], Matrigel [17], acrylic polymers [18], silk [19], hyaluronic acid [20], and ossified tissues [21]. These models have probed the importance of using 3D rather than 2D models to recreate myeloma growth; however, each has its limitations.…”

Three dimensionalde novomicro bone marrow and its versatile application in drug screening and regenerative medicine

“…Beyond this, a 3D model could be used as a clinical tool to inspect skeletal cancer biology and osteogenesis. 42 …”

3D Tissue-Engineered Bone Marrow: What does this Mean for the Treatment of Multiple Myeloma?

“…Significant advances have been made in recreating the myeloma microenvironment in the last decade. Synthetic 3D models have allowed recreating relevant 3D features of the BM and its interactions [13][14][15], and the implantation of fetal bone chips in SCID mice have resemble even better the BM physiology [16]. In addition, in vivo xenograft models of human MM cell lines in SCID mice resembled the interaction of human MM cells with mouse microenvironment [17], while the C57BL/KaLwRij mice represent a syngeneic murine model of MM [18].…”