Reciprocal Interactions between Multiple Myeloma Cells and Osteoprogenitor Cells Affect Bone Formation and Tumor Growth

Abstract : 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 MM growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of MM within the BM are required. We developed a clinically-relevant, 3D myeloma BM co-culture model that mimics bone cell-cancer cell interactions within the bone microenvironment. The co-culture model and clinical samples were utilized to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillary-like assembly of endothelial cells and cell adhesion mediated-drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA 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 the floodgate for novel approaches to cancer. We also further developed the OcnCre/iDTR model and discovered a novel bone marrow adipose tissue (BMAT) phenotype. We then explored reasons for this phenotype, and found evidence that sclerostin derived from osteocytes could potentially be one of the osteokines driving BMAT accumulation. We explored the use of metformin to decrease BMAT. Lastly, we found that using an anti-sclerostin antibody, we were able to decrease tumor burden and increase bone, as well as decrease BMAT, suggesting that this antibody could have a 2-pronged attack on the BM in myeloma.