Abstract 4111: SDF1/CXCR4 regulates stiffness of bone marrow stromal cell through RhoA and Rac1 GTPases pathway to support myeloma cell proliferation in multiple myeloma.

Abstract

Abstract Abstract As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains high incurable and relapse owing to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that are active in drug resistance and target molecular processes of MM progress are attractive. MM is characterized by bone marrow infiltration of malignant plasma cells. The bone marrow microenvironment is a complex structure of various extracellular components and many cell types including haematopoietic stem cells, bone marrow stromal cells (BMSCs), immune cells, bone marrow endothelial cells, as well as osteoclasts and osteoblasts. Recently study showed the physical interaction of multiple myeloma cells with BMSCs from patients of multiple myeloma in the bone marrow milieu, provokes a positive feedback loop and results in multiple myeloma pathogenesis. We observed the myeloma BMSCs are much stiffer and more contractile than normal BMSCs. Stiffer hydrogels support colony formation and adhension of MM better than softer hydrogels. These suggested that myeloma BMSCs provide myeloma cell-friendly microenvironments for myeloma cells via exerting biomechanical forces. In order to elucidate the molecular mechanisms leading to the change of myeloma BMSCs biochemical phenotype, we analyzed myeloma BMSCs and normal BMSCs gene expression profiles. Microarray data analysis demonstrated stromal cell derived factor-1(SDF1) was over expressed in MM BMSCs. In vitro, 100ng/ml SDF1 significantly induced actin polymerization and polarization in MM BMSCs, but not in normal BMSCs. In order to understand how SDF1 regulate BMSCs’ contractile, we conducted reverse phase protein array (RPPA) experiment. Based on RPPA data, we determined RhoA and Rac1 GTPases played important roles in SDF1 induced stiffer of BMSCs. Western blot results also approved SDF1 increased phosphate RhoA and phosphate Rac1 expression level. In conclusion, we characterized the pivotal role of RhoA and Rac1 GTPases in regulating BMSCs stiffness and BMSCs-MM interaction. Targeting biomechanics of BMSCs in myeloma patients, restoring to their normal state would be essential for the long term cure of myeloma, provoking RhoA and Rac1 pathway as novel MM therapy. Citation Format: Dan Wu, Jing Su, Qianqian Song, Xiaobo Zhou. SDF1/CXCR4 regulates stiffness of bone marrow stromal cell through RhoA and Rac1 GTPases pathway to support myeloma cell proliferation in multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2013-4111