CXCR4 Regulates Extra-Medullary Myeloma through Epithelial-Mesenchymal-Transition-like Transcriptional Activation

Abstract

SUMMARY Extra-medullary disease (EMD) in Multiple Myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. However, molecular alterations that lead to EMD have not been well defined. We developed bone marrow (BM)- and EMD-prone MM syngeneic cell lines and identified that epithelial-to-mesenchymal-tranistion (EMT) transcriptional patterns were significantly enriched in the both clones compared to parental cells, together with higher levels of CXCR4 protein; and demonstrated that CXCR4 enhanced the acquisition of an EMT-like phenotype in MM cells with a phenotypic conversion for invasion, leading to higher bone metastasis and EMD dissemination in vivo. In contrast, CXCR4-silencing led to inhibited tumor growth and reduced survival. Ulocuplumab, a monoclonal anti-CXCR4 antibody, inhibited MM cell dissemination, supported by suppression of the CXCR4-driven EMT-like phenotype. These studies suggest that targeting CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression.

Highly Expressed Integrin-α8 Induces Epithelial to Mesenchymal Transition-Like Features in Multiple Myeloma with Early Relapse

“…Considering these data, integrin-α8 mediates the acquisition of EMT properties and induction of CXCR4 expression, which eventually promotes MM cells to migrate and invade to new regions of BM rather than adhere and be retained by the BM microenvironment. Previous observations support our finding that the induction of EMT features enhances CXCR4 expression in epithelial tumors, and that acquisition of EMT-like phenotype with the upregulation of CXCR4 expression develops the extra-medullary in MM, resulting in MM cell dissemination and metastasis (Muz et al, 2014; Roccaro et al, 2015). …”

“…3B). There is growing evidence that the acquisition of EMT-like features accompanied the upregulated CXCR4 expression during MM cell dissemination (Roccaro et al, 2015). The CXCR4/SDF-1α axis plays a major role in chemotaxis in MM cells to BM, and we evaluated CXCR4 expression (Alsayed et al, 2007).…”

[68Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - Comparison to [18F]FDG and laboratory values

“…One hypothesis speculated on potential inferiority of [ 68 Ga]Pentixafor-PET in extramedullary disease due to reduced CXCR4 expression and its critical role in cell homing 18, 19. Another recent publication hinted at a special role of CXCR4 in the acquisition of an epithelial-to-mesenchymal transition-like phenotype, which promotes MM cell dissemination 20.…”

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

“…For these models, the researcher must decide what to use in terms of the tumour cell line (or primary cells), the model for bone metastasis or growth in the bone marrow, the mouse model and/or strain, and the methods to track tumour burden and bone parameters. Examples of commonly used models of metastasis to the host bone morrow are intravenous injection of the myeloma cell line MM.1S, 133,158 intracardiac injection of the breast cancer cell line MDA-MB-231, 159,160 and intracardiac injection of the prostate cancer cell line PC-3. 161 An advantage of these models is that they recapitulate the latter stages of bone marrow metastasis, including circulation of tumour cells through the bloodstream, rolling and arrest at a distant bone marrow capillary, extravasation across the endothelial lining, colonization of the new microenvironment, proliferation, and hijacking and reprogramming of the bone marrow.…”