title: CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway.
abstract: As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied. In our study, we found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138⁻ myeloma cells, but not CD138⁺ cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138⁻ myeloma subpopulation compared with that in CD138⁺ cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138⁻ myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138⁻ myeloma cell-directed cross-talk with BMSCs and reveal that CD138⁻ myeloma cells regulate M-BMSC stiffness through SDF-1/CXCR4/AKT signaling.
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Ruoying
authors.initials: R
authors.lastname: Chen
authors.affiliation: Hematology & Oncology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Berenzon
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Guthold
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Bonin
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Weiling
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Electronic address: xizhou@wfubmc.edu.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
mesh_terms: D001696:Biomechanical Phenomena; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D018994:Myosin Light Chains; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D053668:Syndecan-1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein
keywords: AKT; Bone marrow stromal cell; CD138-negative; Multiple myeloma; SDF-1/CXCR4; Stiffness