title: CXCR4 Regulates Extra-Medullary Myeloma through Epithelial-Mesenchymal-Transition-like Transcriptional Activation.
abstract: 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; 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Maine Medical Center Research Institute (MMCRI), Scarborough, ME 04074, USA.
authors.forename: Michaela R
authors.initials: MR
authors.lastname: Reagan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Huynh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yawara
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ilyas
authors.initials: I
authors.lastname: Sahin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Spedali Civili di Brescia, Centro per la Ricerca Onco-ematologica AIL (CREA), 25123 Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chiarini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Salomon
authors.initials: S
authors.lastname: Manier
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yosra
authors.initials: Y
authors.lastname: Aljawai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Glavey
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, MA 02215, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Morgan
authors.affiliation: Bristol-Myers Squibb, Redwood City, CA 94063, USA.
authors.forename: Chin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Bristol-Myers Squibb, Redwood City, CA 94063, USA.
authors.forename: Pina
authors.initials: P
authors.lastname: Cardarelli
authors.affiliation: Bristol-Myers Squibb, Redwood City, CA 94063, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kuhne
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: irene_ghobrial@dfci.harvard.edu.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000556:secondary; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023981:Sarcoma, Myeloid / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015533:Transcriptional Activation
chemical_list: D000911:Antibodies, Monoclonal; D019718:Receptors, CXCR4