TY - JOUR
T1 - Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment
AU - Matamala Montoya, María
AU - van Slobbe, Gijs J. J.
AU - Chang, Jung-Chin
AU - Zaal, Esther A.
AU - Berkers, Celia R.
N1 - Funding Information: We kindly thank Jeroen Jansen at the Utrecht Metabolism Expertise Centre (Faculty of Veterinary Medicine, Utrecht University) for technical assistance with mass spectrometry experiments, Estefania Lozano Andres of the Flow Cytometry and Cell sorting facility of the Faculty of Veterinary Medicine (Utrecht University) and Miranda Triest from Universitair Medisch Centrum Utrecht for assistance with the Seahorse assay. Publisher Copyright: Copyright © 2023 Matamala Montoya, van Slobbe, Chang, Zaal and Berkers.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Bortezomib
KW - bone marrow stromal cell (BMSC)
KW - cancer metabolism
KW - drug resistance
KW - fluxomics
KW - metabolomics
KW - multiple myeloma
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85153527155&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fonc.2023.1155621
DO - https://doi.org/10.3389/fonc.2023.1155621
M3 - Article
C2 - 37091139
SN - 2234-943X
VL - 13
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1155621
ER -