Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma

In carcinoma, cancer-associated fibroblasts participate in force-mediated extracellular matrix (ECM) remodeling, consequently leading to invasion of cancer cells. Likewise, the ECM remodeling actively occurs in glioblastoma (GBM) and the consequent microenvironmental stiffness is strongly linked to migration behavior of GBM cells. However, in GBM the stromal cells responsible for force-mediated ECM remodeling remain unidentified. We show that tumor-associated mesenchymal stem-like cells (tMSLCs) provide a preinvasive matrix condition in GBM by force-mediated ECM remodeling. Importantly, CCL2-mediated Janus kinase 1 (JAK1) activation increased phosphorylation of myosin light chain 2 in tMSLCs and led to collagen assembly and actomyosin contractility. Collectively, our findings implicate tMSLCs as stromal cells providing force-mediated preinvasive ECM remodeling in the GBM microenvironment, and reminiscent of fibroblasts in carcinoma.We thank Akio Soeda (Department of Neurological Surgery, Gifu University, Japan) for providing patient-derived X01 GBM cells. This work was supported by the research fund of Hanyang University (HY-2017) and by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean Government (NRF-2016R1E1A1A01942075)