Matrix stiffness mediates glioma cells stemness through an integrin/JAK/STAT3 signaling pathway

Abstract Background：Matrix stiffness in tumor microenvironment is tightly correlated with the tumor progression in solid cancer. However, the potential role of matrix stiffness in glioma progression remains controversial. Our study aimed to explore the underlying mechanism of glioma progression induced by matrix stiffness. Methods: Atomic force microscopy analysis was performed to examine the stiffness of tumor tissues. tunable polyacrylamide (PA) hydrogels were used for cells culture with different matrix stiffness. CCK-8 analysis was used to examine the cells proliferation. Colony formation analysis and subcutaneous tumor-bearing mice model were used to detect the capability of tumorigenesis. Western blotting and immunofluorescent staining were performed to examine the signals activation in glioma cells. Results: In our study, we observed a higher matrix stiffness in high degree glioma tissues from patients. We demonstrated that a higher stiffness culture system could mediate the upregulation of stemness in glioma cells, resulting in the strengthen capability of tumor growth and relapse in glioma. In mechanism, we observed activation of integrin α5β1/JAK1/STAT3/c-Myc signaling pathway in glioma cells under the simulation of a higher matrix stiffness. Combination of STAT3 inhibitor STAT3-IN-1 and chemotherapeutic temozolomide (TMZ) obviously suppressed the xenogenous glioma mice model, which revealed strengthen anticancer effects and improved outcome.Conclusion: We demonstrated that a higher matrix stiffness could promote glioma progression through an integrin α5β1/JAK1/STAT3/c-Myc signaling pathway. Blockade of STAT3 signals improved the anticancer effects of chemotherapy, providing new insights for glioma therapy in clinic.