Extracellular matrix stiffness conditions glioblastoma cells for long-term migration: Mechanical memory as a driver of invasion and recurrence in glioblastoma

Extracellular matrix (ECM) stiffening correlates with tumor invasion in various cancer types, including glioblastoma (GBM). Increased matrix stiffness promotes a migratory phenotype through dysregulation of cell-ECM bidirectional communication. Exposure to stiffer environments is sensed by cells, which then adapt in ways that promote invasive behavior. These adaptive changes are imprinted onto the cells and persist even after they are placed in new, softer microenvironments via a process known as "mechanical memory." Mechanical memory is believed to be driven by mechanosensitive transcription factor activity and epigenetic remodeling. Glioblastoma recurrence is linked to the ability of cells to disperse and infiltrate the surrounding healthy tissue. Extracellular matrix stiffness in GBM is heterogeneous; it starts with a softer tumor core and becomes progressively stiffer toward the tumor's edges, potentially promoting sustained tumor invasion through mechanical memory. This review discusses the role of ECM stiffness in cancer cell behavior and the implications of ECM stiffening in GBM. We then describe the findings associated with mechanical memory and relay underlying mechanisms currently understood to drive the preservation of mechanically primed phenotypes. Finally, we discuss how matrix stiffness can drive migratory phenotypes in GBM cells and the potential role that progressive ECM dysregulation at the tumor periphery can link the formation of invasive tumor niches to the aggressive, resistant, and mesenchymal-like phenotypes present in GBM recurrent tumors.