Journal Article

CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment

Lazzarino Giacomo, Dulcamare Ilaria, Musumeci Giuseppe, Amorini, Angela Maria, Scandura Grazia, Parenti Rosalba, Tibullo Daniele, Oteri Rosaria, Del Fabro Vittorio, Palumbo, Giuseppe A, Giallongo Cesarina, Aguennouz M’hammed, Li Volti Giovanni, Conticello Concetta, Di Raimondo Francesco, Romano, Alessandra, Di Rosa Michelino, Vicario Nunzio, Polito, Francesca, Parrinello Nunziatina

2022

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Biopsy / Bortezomib / Cell interactions / Chemoresistance / Connexin 43 / CXCL12 protein / CXCR4 protein / Inhibitor drugs / Mesenchyme / Microenvironments / Mitochondria / Multiple myeloma / Patients / Phenotypes / Plasma cells / Stromal cells / Tumors