System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance

Fang Wang; Inge Oudaert; Chenggong Tu; Anke Maes; Arne Van der Vreken; Philip Vlummens; Elke De Bruyne; Kim De Veirman; Yanmeng Wang; Rong Fan; Ann Massie; Karin Vanderkerken; Peng Shang; Eline Menu

doi:10.1016/j.canlet.2022.215649

System Xc⁻ inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance

Fang Wang, Inge Oudaert, Chenggong Tu, Anke Maes, Arne Van der Vreken, Philip Vlummens, Elke De Bruyne, Kim De Veirman, Yanmeng Wang, Rong Fan, Ann Massie, Karin Vanderkerken, Peng Shang, Eline Menu

School of life sciences

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Article number	215649
Journal	Cancer Letters
Volume	535
DOIs	https://doi.org/10.1016/j.canlet.2022.215649
State	Published - 1 Jun 2022

Keywords

Bone marrow
Exosome
Glutamate
Multiple myeloma
System Xc

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.canlet.2022.215649

Cite this

Wang, F., Oudaert, I., Tu, C., Maes, A., Van der Vreken, A., Vlummens, P., De Bruyne, E., De Veirman, K., Wang, Y., Fan, R., Massie, A., Vanderkerken, K., Shang, P., & Menu, E. (2022). System Xc⁻ inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance. Cancer Letters, 535, Article 215649. https://doi.org/10.1016/j.canlet.2022.215649

@article{fd8f60f5289948ceaa4f2523612e0dda,

title = "System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance",

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.",

keywords = "Bone marrow, Exosome, Glutamate, Multiple myeloma, System Xc",

author = "Fang Wang and Inge Oudaert and Chenggong Tu and Anke Maes and {Van der Vreken}, Arne and Philip Vlummens and {De Bruyne}, Elke and {De Veirman}, Kim and Yanmeng Wang and Rong Fan and Ann Massie and Karin Vanderkerken and Peng Shang and Eline Menu",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jun,

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doi = "10.1016/j.canlet.2022.215649",

language = "英语",

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Wang, F, Oudaert, I, Tu, C, Maes, A, Van der Vreken, A, Vlummens, P, De Bruyne, E, De Veirman, K, Wang, Y, Fan, R, Massie, A, Vanderkerken, K, Shang, P & Menu, E 2022, 'System Xc⁻ inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance', Cancer Letters, vol. 535, 215649. https://doi.org/10.1016/j.canlet.2022.215649

TY - JOUR

T1 - System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance

AU - Wang, Fang

AU - Oudaert, Inge

AU - Tu, Chenggong

AU - Maes, Anke

AU - Van der Vreken, Arne

AU - Vlummens, Philip

AU - De Bruyne, Elke

AU - De Veirman, Kim

AU - Wang, Yanmeng

AU - Fan, Rong

AU - Massie, Ann

AU - Vanderkerken, Karin

AU - Shang, Peng

AU - Menu, Eline

PY - 2022/6/1

Y1 - 2022/6/1

N2 - 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.

AB - 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.

KW - Bone marrow

KW - Exosome

KW - Glutamate

KW - Multiple myeloma

KW - System Xc

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U2 - 10.1016/j.canlet.2022.215649

DO - 10.1016/j.canlet.2022.215649

M3 - 文章

C2 - 35315341

AN - SCOPUS:85126928657

SN - 0304-3835

VL - 535

JO - Cancer Letters

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