title: SDF-1α stiffens myeloma bone marrow mesenchymal stromal cells through the activation of RhoA-ROCK-Myosin II.
abstract: Multiple myeloma (MM) is a B lymphocyte malignancy that remains incurable despite extensive research efforts. This is due, in part, to frequent disease recurrences associated with the persistence of myeloma cancer stem cells (mCSCs). Bone marrow mesenchymal stromal cells (BMSCs) play critical roles in supporting mCSCs through genetic or biochemical alterations. Previously, we identified mechanical distinctions between BMSCs isolated from MM patients (mBMSCs) and those present in the BM of healthy individuals (nBMSCs). These properties of mBMSC contributed to their ability to preferentially support mCSCs. To further illustrate mechanisms underlying the differences between mBMSCs and nBMSCs, here we report that (i) mBMSCs express an abnormal, constitutively high level of phosphorylated Myosin II, which leads to stiffer membrane mechanics, (ii) mBMSCs are more sensitive to SDF-1α-induced activation of MYL2 through the G(i./o)-PI3K-RhoA-ROCK-Myosin II signaling pathway, affecting Young's modulus in BMSCs and (iii) activated Myosin II confers increased cell contractile potential, leading to enhanced collagen matrix remodeling and promoting the cell-cell interaction between mCSCs and mBMSCs. Together, our findings suggest that interfering with SDF-1α signaling may serve as a new therapeutic approach for eliminating mCSCs by disrupting their interaction with mBMSCs.
authors.affiliation: Methodist Cancer Center, Houston Methodist Hospital, Houston, TX.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Choi
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stark
authors.forename: Robert M
authors.initials: RM
authors.lastname: Raphael
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.forename: Chung-Che
authors.initials: CC
authors.lastname: Chang
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
mesh_terms: D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002448:Cell Adhesion; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D024462:Myosin Type II / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; C066737:RHOA protein, human; D019869:Phosphatidylinositol 3-Kinases; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D024462:Myosin Type II; D020742:rhoA GTP-Binding Protein
keywords: RhoA-ROCK-Myosin II; SDF-1α; mesenchymal stromal cells; multiple myeloma