Bone marrow adipocytes is a new player in supporting myeloma cells proliferation and survival in myeloma microenvironment

Xiaoqian Wei; Yangmin Zhang; Ziyan Wang; Yuanning He; Songguang Ju; Jinxiang Fu

doi:10.1016/j.tranon.2023.101856

Bone marrow adipocytes is a new player in supporting myeloma cells proliferation and survival in myeloma microenvironment

Transl Oncol. 2024 Feb:40:101856. doi: 10.1016/j.tranon.2023.101856. Epub 2023 Dec 21.

Authors

Xiaoqian Wei¹, Yangmin Zhang¹, Ziyan Wang¹, Yuanning He¹, Songguang Ju², Jinxiang Fu³

Affiliations

¹ Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, PR China.
² Institute of Biotechnology, Soochow University, Suzhou 215007, PR China.
³ Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, PR China. Electronic address: fujinxiang@suda.edu.cn.

Abstract

Multiple myeloma (MM) is a lethal B cell neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow and remains incurable due to disease relapse and drug resistance. Bone marrow adipocytes (BMAs) are emerging as playing active functions that can support myeloma cell growth and survival. The aim of this study is to investigate myeloma-mesenchymal stem cells (MSCs) interaction and the impact of such interactions on the pathogenesis of MM using in vitro co-culture assay. Here we provide evidence that MM cell up-regulated MSCs to express PPAR-γ and pushes MSCs differentiation toward adipocytes at the expense of osteoblasts in co-culture manner. The increased BMAs can effectively enhance MM cell to proliferation, migration, and chemoresistance via cell-cell contact and/or cytokines release regulated by PPAR-γ signal pathway. This effect was partially reversed in medium containing PPAR-γ antagonist G3335 and indicated that G3335 distorts the maturation of MSC-derived adipocytes and cytokines release by adipocytes through inhibition of PPAR-γ, a key transcriptional factor for the activation of adipogenesis, or cell to cell contact, or both. In meantime, we observed higher expression of adipocyte differentiation associated genes DLK1, DGAT1, FABP4, and FASN both in MSCs and MSC derived adipocytes, but the osteoblast differentiation-associated gene ALP was down regulated in MSCs. These finding mean that direct consequence of MM/MSC interaction that play a role in MM pathogenesis. Consistent with those in vitro results, our primary clinical observation also showed that bone marrow samples from MM patients had significantly higher bone adiposity in comparison with controls and the number of adipocytes decreased in those who were response to anti-MM therapy. Our finding suggested that BMAs may have an important contribution to MM progression, particularly in drugs resistant of MM cells, and plays an important contribution in MM bone disease and treatment failure, but more clinical studies are needed to confirm its role.

Keywords: Drug resistance; Mesenchymal stem cells; Multiple myeloma; Myeloma associated adipocytes; Survival.