Pyruvate from bone marrow mesenchymal stem cells supports myeloma redox homeostasis and anabolism

Elías Vera-Sigüenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Charlotte Speakman, Alejandro Huerta-Uribe, Lisa Vettore, Himani Rana, Adam Boufersaoui, Hans Vellama, Ramin Nashebi, Ielyaas Cloete, Jennie Roberts, Supratik Basu, Mark Drayson, Christopher Bunce, Guy Pratt, Fabian Spill, Oliver D.K. Maddocks, Daniel A. Tennant
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Abstract

Multiple myeloma is an incurable cancer of plasma cells that depends on the bone marrow for its survival. Despite its prevalence, the molecular mechanisms underlying this malignancy remain poorly understood. In this study, we aim to bridge this knowledge gap by elucidating the metabolic interplay between myeloma cells and bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are crucial in supporting myeloma cell metabolism, contributing to their proliferation, survival, and resistance to chemotherapy. Through a combination of mathematical modelling and experimental co-cultures, we demonstrate that pyruvate – the end product of glycolysis – plays a key role in myeloma cell metabolism. Our findings reveal that myeloma cells predominantly rely on the uptake of pyruvate produced by neighbouring BMM-SCs via the plasma membrane proton-linked monocarboxylate transporters MCT-1 and MCT-2 encoded by the Slc16a1 and a2 genes, respectively. Furthermore, we show that pharmacological inhibition of the MCT-1/2, with AZD3965, triggers a cascade of compensatory metabolic responses, disrupting redox balance and significantly reducing the proliferation capacity of co-cultured myeloma cells.
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骨髓间充质干细胞产生的丙酮酸支持骨髓瘤的氧化还原平衡和合成代谢
多发性骨髓瘤是一种无法治愈的浆细胞癌症,依靠骨髓存活。尽管多发性骨髓瘤很常见,但人们对这种恶性肿瘤的分子机制仍然知之甚少。在这项研究中,我们旨在通过阐明骨髓瘤细胞与骨髓间充质干细胞(BMMSCs)之间的新陈代谢相互作用来弥补这一知识空白。骨髓间充质干细胞对支持骨髓瘤细胞的新陈代谢至关重要,有助于它们的增殖、存活和对化疗的抵抗。通过数学建模和实验共培养相结合的方法,我们证明了丙酮酸--糖酵解的最终产物--在骨髓瘤细胞的新陈代谢中起着关键作用。我们的研究结果表明,骨髓瘤细胞主要依赖于通过分别由 Slc16a1 和 a2 基因编码的质膜质子连接单羧酸盐转运体 MCT-1 和 MCT-2 吸收邻近 BMM-SC 产生的丙酮酸盐。此外,我们还发现,用 AZD3965 对 MCT-1/2 进行药理抑制,会引发一连串的代偿代谢反应,破坏氧化还原平衡,显著降低共培养骨髓瘤细胞的增殖能力。
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