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Updated: Sep 29, 2025
Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
System Xc- inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib
Fang Wang1, Inge Oudaert2, Chenggong Tu2
1School of Life Science, Northwestern Polytechnical University, Xi'an, 710072, PR China; Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, B-1090, Belgium.
Abstract:
Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc-). Extracellular glutamate released by system Xc- can bind to glutamate metabotropic receptor (GRM) 3, thereby upregulating Rab27-dependent vesicular trafficking. Since Rab27 is also involved in exosome biogenesis, we aimed to investigate the role of system Xc- in exosomal communication between BM stromal cells (BMSCs) and MM cells. We observed that expression of xCT and GRMs was increased after bortezomib treatment in both BMSCs and MM cells. Secretion of glutamate and exosomes was simultaneously enhanced which could be countered by inhibition of system Xc- or GRMs. Moreover, glutamate supplementation increased exosome secretion by increasing expression of Alix, TSG101, Rab27a/b and VAMP7. Importantly, the system Xc- inhibitor sulfasalazine reduced BMSC-induced resistance to bortezomib in MM cells in vitro and enhanced its anti-MM effects in vivo. These findings suggest that system Xc- plays an important role within the BM and could be a potential target in MM.
Insights
System Xc- influences multiple myeloma cell growth by mediating exosomal communication. Inhibiting this system, along with glutamate receptors, may overcome bortezomib resistance and improve treatment efficacy.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Multiple myeloma (MM) cells rely on bone marrow (BM) microenvironment signals for proliferation, often through exosomal communication.
- Bortezomib resistance in MM is associated with increased expression of the xCT subunit of system Xc-.
- Extracellular glutamate, released by system Xc-, can activate glutamate metabotropic receptors (GRMs), influencing vesicular trafficking and exosome release.
Purpose of the Study:
- To investigate the role of system Xc- in mediating exosomal communication between bone marrow stromal cells (BMSCs) and MM cells.
- To explore system Xc- as a potential therapeutic target for overcoming bortezomib resistance in MM.
Main Methods:
- Assessed expression of xCT and GRMs in BMSCs and MM cells following bortezomib treatment.
- Measured glutamate and exosome secretion, and their modulation by system Xc- and GRM inhibitors.
- Investigated the effect of glutamate supplementation on exosome secretion markers (Alix, TSG101, Rab27a/b, VAMP7).
- Evaluated the efficacy of the system Xc- inhibitor sulfasalazine in vitro and in vivo.
Main Results:
- Bortezomib treatment upregulated xCT and GRM expression in both BMSCs and MM cells, enhancing glutamate and exosome secretion.
- Inhibition of system Xc- or GRMs reduced glutamate and exosome secretion.
- Glutamate supplementation increased exosome secretion by upregulating key exosome biogenesis proteins.
- Sulfasalazine treatment decreased BMSC-induced bortezomib resistance in MM cells in vitro and improved anti-MM effects in vivo.
Conclusions:
- System Xc- plays a significant role in the BM microenvironment's support of MM cells.
- Targeting system Xc- can disrupt pro-survival exosomal communication and overcome bortezomib resistance.
- System Xc- represents a promising therapeutic target for multiple myeloma treatment.
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