Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

Abstract

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.

Deciphering metabolic crosstalk in context: lessons from inflammatory diseases

“…2C), providing information on pathway dynamics in cell populations (Table 1). Stable isotope tracing has been pivotal in studying pathway dynamics and understanding metabolic switches in many immune cell types [98][99][100][101][102][103][104][105]. For example, Mensink et al [100] recently performed tracing experiments using 13 C 6 -glucose and 13 C 5 -glutamine to determine the effect of tumor necrosis factor receptor 2 (TNRF2) co-stimulation on CD4 + conventional and regulatory T cells.…”

“…Using this system, the authors found that cytokines (IL-6) and chemokines (CCL5, CXCL10) secreted by cancer-associated fibroblasts induce glycogen breakdown in ovarian cancer cells to promote proliferation and invasion [106]. Using 13 C 6glucose tracing in combination with a Transwell coculture system, Matamala Montoya et al [101] recently demonstrated the importance of bone-marrow stromal cells in inducing drug resistance-associated metabolic rewiring in multiple myeloma. To map cell-type-specific dynamic changes in central carbon metabolism, Wang et al [107] applied an advanced high-spatial-resolution metabolomics approach using MALDI-MSI combined with isotope tracing in an organoid co-culture.…”

“…2C ), providing information on pathway dynamics in cell populations (Table 1 ). Stable isotope tracing has been pivotal in studying pathway dynamics and understanding metabolic switches in many immune cell types [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. For example, Mensink et al.…”

“…Using 13 C 6 ‐glucose tracing in combination with a Transwell co‐culture system, Matamala Montoya et al. [ 101 ] recently demonstrated the importance of bone‐marrow stromal cells in inducing drug resistance‐associated metabolic rewiring in multiple myeloma. To map cell‐type‐specific dynamic changes in central carbon metabolism, Wang et al.…”

Lipid metabolic vulnerabilities of multiple myeloma

“…Mitochondrial alterations, with increased biomass as well as unbalanced mitochondrial functions, can prompt metabolic changes which have been found instrumental in MM onset and chemoresistance [ 6 , 16 , 17 ]. MM cells are strictly dependent on glucose metabolism by enhancing glucose uptake and aerobic glycolysis and producing lactate, providing an important carbon source for tricarboxylic acid (TCA) cycle and OXPHOS, required to maintain elevated protein synthesis, folding and secretion.…”