CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment.
Cesarina GiallongoIlaria DulcamareDaniele TibulloVittorio Del FabroNunzio VicarioNunziatina ParrinelloAlessandra RomanoGrazia ScanduraGiacomo LazzarinoConcetta ConticelloGiovanni Li VoltiAngela Maria AmoriniGiuseppe MusumeciMichelino Di RosaFrancesca PolitoRosaria OteriM'hammed AguennouzRosalba ParentiFrancesco Di RaimondoGiuseppe Alberto Maria PalumboPublished in: Oncogenesis (2022)
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.
Keyphrases
- multiple myeloma
- newly diagnosed
- induced apoptosis
- cell cycle arrest
- oxidative stress
- cell death
- ejection fraction
- poor prognosis
- stem cells
- endoplasmic reticulum stress
- prognostic factors
- bone marrow
- signaling pathway
- long non coding rna
- pi k akt
- umbilical cord
- patient reported outcomes
- big data
- ultrasound guided
- cancer stem cells
- fine needle aspiration