Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

Frontiers in Oncology

Oncology

Gijs J. J. van Slobbe¹  Celia R. Berkers¹  Esther A. Zaal¹  Jung-Chin Chang¹  María Matamala Montoya² 

[1] Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands;Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands;Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands;

关键词: cancer metabolism;    multiple myeloma;    drug resistance;    bone marrow stromal cell (BMSC);    fluxomics;    metabolomics;    tumor microenvironment;    Bortezomib;   

DOI  :  10.3389/fonc.2023.1155621

 received in 2023-01-31, accepted in 2023-03-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drug-resistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy.

【 授权许可】

Unknown   
Copyright © 2023 Matamala Montoya, van Slobbe, Chang, Zaal and Berkers