The antidiabetic drug metformin acts on the bone microenvironment to promote myeloma cell adhesion to preosteoblasts and increase myeloma tumour burden in vivo

Beatriz Gámez,Emma V Morris,Sam W.Z Olechnowicz,Siobhan Webb,James R Edwards,Aneka Sowman,Christina J Turner,Claire M Edwards

doi:10.1016/j.tranon.2021.101301

Abstract

Multiple myeloma is a haematological malignancy that is dependent upon interactions within the bone microenvironment to drive tumour growth and osteolytic bone disease. Metformin is an anti-diabetic drug that has attracted attention due to its direct antitumor effects, including anti-myeloma properties. However, the impact of the bone microenvironment on the response to metformin in myeloma is unknown. We have employed in vitro and in vivo models to dissect out the direct effects of metformin in bone and the subsequent indirect myeloma response. We demonstrate how metformin treatment of preosteoblasts increases myeloma cell attachment. Metformin-treated preosteoblasts increased osteopontin (OPN) expression that upon silencing, reduced subsequent myeloma cell adherence. Proliferation markers were reduced in myeloma cells cocultured with metformin-treated preosteoblasts. In vivo, mice were treated with metformin for 4 weeks prior to inoculation of 5TGM1 myeloma cells. Metformin-pretreated mice had an increase in tumour burden, associated with an increase in osteolytic bone lesions and elevated OPN expression in the bone marrow. Collectively, we show that metformin increases OPN expression in preosteoblasts, increasing myeloma cell adherence. In vivo, this translates to an unexpected indirect pro-tumourigenic effect of metformin, highlighting the importance of the interdependence between myeloma cells and cells of the bone microenvironment.

Highlights

Multiple myeloma is a B-cell malignancy characterised by an expansion of clonal plasma cells within the bone marrow
Given the interdependence of myeloma cells with the bone microenvironment, with bone-lining osteoblasts, and the conflicting reports of metformin in bone biology, we aimed to investi gate whether metformin could have an indirect effect in myeloma via bone cells
In the current work we show how metformin acts upon preosteoblasts to increase the subsequent adhesion of myeloma cells, with this indirect effect on myeloma cells dependent, at least in part, upon elevated OPN levels in metformin-treated preosteoblasts

Summary

Introduction

Multiple myeloma is a B-cell malignancy characterised by an expansion of clonal plasma cells within the bone marrow. This coloni zation leads to bone marrow failure, anaemia and the characteristic osteolytic bone lesions associated with disease progression [1]. A retrospective study of U.S vet erans with diabetes mellitus prior to MGUS diagnosis identified a reduction in MGUS progression to myeloma when metformin was consistently used for at least 4 years [12]. There is accumulating in vitro and in vivo evidence for a direct anti-tumour effect of metformin in myeloma, preclinical in vivo studies were limited to subcu taneous models and the critical influence of the bone marrow

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