Choi, Dong Soon, Stark, Daniel J., Raphael, Robert M., Wen, Jianguo, Su, Jing, Zhou, Xiaobo, Chang, Chung-Che, Zu, Youli
funding text
Grant sponsor: NIH; Grant numbers: R01CA151955, R33CA173382; Grant sponsor: NIH/NLM; Grant number: 5R01LM010185
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-1-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-1 signaling may serve as a new therapeutic approach for eliminating mCSCs by disrupting their interaction with mBMSCs. What's new? Multiple myeloma remains an uncurable disease in part because of the persistence of myeloma cancer stem cells that remain in specific niches in the bone marrow. Here, the authors established a novel function of stromal cell-derived factor (SDF)-1 in altering biomechanics of myeloma-associated bone marrow mesenchymal stromal cells through the activation of myosin II. They further determined that the altered biophysical characteristics play a critical role in regulating the interactions between the stroma and myeloma cancer stem cells. Collectively, the results suggest that matrix stiffening can occur in the bone marrow of multiple myeloma patients which in turn can promote disease pathogenesis.