CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment

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

doi:10.1038/s41389-022-00380-z

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.

Highlights

Multiple myeloma (MM) is a malignancy of plasma cells (PCs) that accumulate within the bone marrow (BM) and is associated with monoclonal protein in serum and/or urine
This different metabolic phenotype showed by MM-Mesenchymal stromal cells (MSCs) was not related to alterations of the energy state as suggested by similar values of Energy charge potential (ECP) observed in HC- and MM-MSCs (Fig. 1C)
Given that connexin 43 (CX43) is involved in mitochondria trafficking, we subsequently evaluated whether its inhibition decreased mito- CXCR4 inhibition reduces mitochondrial transfer from MSCs to chondria uptake in tumor PCs

Summary

Introduction

Multiple myeloma (MM) is a malignancy of plasma cells (PCs) that accumulate within the bone marrow (BM) and is associated with monoclonal protein in serum and/or urine. We and others have previously described a significant different phenotype of MM-MSCs compared to MSC from healthy donors [5,6,7,8], according to their remodeling in a pathological niche To this regard, it has been demonstrated that interferon-responsive effector T cell and CD8+ stem cell memory T cell populations release proinflammatory cytokines activating myeloma-specific inflammatory MSCs [9]. It has been demonstrated that interferon-responsive effector T cell and CD8+ stem cell memory T cell populations release proinflammatory cytokines activating myeloma-specific inflammatory MSCs [9] These inflammatory stromal cells colocalize with tumor PCs and their gene signature promotes myeloma survival and impact on the immune system functioning. Chronic inflammation within the tumor niche leads MM-MSCs to activate TLR4 signaling, which polarizes them toward a protumorigenic phenotype, favoring immunosuppression and tumor growth [7]

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