Portal de Periódicos da CAPES

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

2015; Cell Press; Volume: 12; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2015.06.059

2639-1856

Aldo M. Roccaro, Yuji Mishima, Antonio Sacco, Michele Moschetta, Yu‐Tzu Tai, Jiantao Shi, Yong Zhang, Michaela R. Reagan, Daisy Huynh, Yawara Kawano, İlyas Şahin, Marco Chiarini, Salomon Manier, Michele Cea, Yosra Aljawai, Siobhan Glavey, Elizabeth A. Morgan, Chin Pan, Franziska Michor, Pina M. Cardarelli, Michelle Kuhne, Irene M. Ghobrial,

Cell Adhesion Molecules Research

Highlights•CXCR4 mediates extra-medullary multiple myeloma (MM)•CXCR4 enhances EMT-like phenotype acquisition in MM•Ulocuplumab inhibits MM cell dissemination and EMT acquisition in MMSummaryExtra-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; identified that epithelial-to-mesenchymal transition (EMT) transcriptional patterns were significantly enriched in 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 results 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.Graphical abstract