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CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment

Authors :
Cesarina Giallongo
Ilaria Dulcamare
Daniele Tibullo
Vittorio Del Fabro
Nunzio Vicario
Nunziatina Parrinello
Alessandra Romano
Grazia Scandura
Giacomo Lazzarino
Concetta Conticello
Giovanni Li Volti
Angela Maria Amorini
Giuseppe Musumeci
Michelino Di Rosa
Francesca Polito
Rosaria Oteri
M’hammed Aguennouz
Rosalba Parenti
Francesco Di Raimondo
Giuseppe A. Palumbo
Source :
Oncogenesis, Vol 11, Iss 1, Pp 1-13 (2022)
Publication Year :
2022
Publisher :
Nature Publishing Group, 2022.

Abstract

Abstract Mesenchymal stromal cells (MSCs) within the protective microenvironment of multiple myeloma (MM) promote tumor growth, confer chemoresistance and support metabolic needs of plasma cells (PCs) even transferring mitochondria. In this scenario, heterocellular communication and dysregulation of critical signaling axes are among the major contributors to progression and treatment failure. Here, we report that myeloma MSCs have decreased reliance on mitochondrial metabolism as compared to healthy MSCs and increased tendency to deliver mitochondria to MM cells, suggesting that this intercellular exchange between PCs and stromal cells can be consider part of MSC pro-tumorigenic phenotype. Interestingly, we also showed that PCs promoted expression of connexin 43 (CX43) in MSCs leading to CXCL12 activation and stimulation of its receptor CXCR4 on MM cells favoring protumor mitochondrial transfer. Consistently, we observed that selective inhibition of CXCR4 by plerixafor resulted in a significant reduction of mitochondria trafficking. Moreover, intracellular expression of CXCR4 in myeloma PCs from BM biopsy specimens demonstrated higher CXCR4 colocalization with CD138+ cells of non-responder patients to bortezomib compared with responder patients, suggesting that CXCR4 mediated chemoresistance in MM. Taken together, our data demonstrated that CXCL12/CXCR4 axis mediates intercellular coupling thus suggesting that the myeloma niche may be exploited as a target to improve and develop therapeutic approaches.

Details

Language :
English
ISSN :
21579024
Volume :
11
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Oncogenesis
Publication Type :
Academic Journal
Accession number :
edsdoj.79bf21d64e74e5397815d288ee2e4c3
Document Type :
article
Full Text :
https://doi.org/10.1038/s41389-022-00380-z