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

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

Transl Oncol. 2022 Jan;15(1):101301. doi: 10.1016/j.tranon.2021.101301. Epub 2021 Dec 8.

Authors

Beatriz Gámez¹, Emma V Morris¹, Sam W Z Olechnowicz², Siobhan Webb³, James R Edwards², Aneka Sowman², Christina J Turner³, Claire M Edwards⁴

Affiliations

¹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Centre for Translational Myeloma Research, University of Oxford, Oxford, UK.
² Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
³ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁴ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Centre for Translational Myeloma Research, University of Oxford, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. Electronic address: claire.edwards@ndorms.ox.ac.uk.

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.

Keywords: Bone microenvironment; Metformin; Myeloma; Osteoblast; Osteopontin.

Abstract

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