Myeloma Cells Self-promote Migration by Regulating TAB1-driven TIMP-1 Expression in Mesenchymal Stem Cells

Multiple myeloma (MM) is an intractable hematological malignancy characterized by abnormal plasma cells in the bone marrow (BM) and increased osteolytic lesions. Within the BM niche, mesenchymal stem cells (MSCs) have been proposed to contribute to functionally important MM-MSC interactions. However, despite various studies on MM pathology, the impact of MM on MSCs during the early stages of malignancy has not been adequately addressed. We previously identified tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) as a cytokine that is modulated in vivo within the MM BM niche, and highlighted its potential relevance in MM. Given the role of TIMP-1 in preventing migration of breast cancer cells, this study aimed to investigate the relationship between MSC-secreted TIMP-1 and MM progression. Here, we examined the effect of MSC-derived TIMP-1 on MM cell migration, and found that TIMP-1 secreted by human MSCs play a role in preventing migration of MM cells by reducing the levels of MM cell-derived MMP-9. We also investigated how MM cells regulate expression of TIMP-1 in MSCs. Using a knockdown approach in MSCs, we implicated TGF-B activated kinase 1 binding protein 1 (TAB1) as an upstream effector of TIMP-1 that was downregulated in the presence of MM cells, which resulted in reduced TIMP-1 secretion. Overall, our findings uncover how MSCs in the MM BM niche are modulated to promote MM progression, and unravel a previously unreported role of the TAB1-TIMP-1 axis in the context of the MM BM niche.