Exploring the Role of Substrate Stiffness in Aggressiveness of Recurrent Glioblastoma

We studied how the physical substrate stiffness on which the cells grow affects the aggressiveness of recurrent glioblastoma. This study helped us to discover that when parent and recurrent GBM cells were grown on a substrate with brain-like stiffness, the recurrent cells were more aggressive than the parent cells. This aggressive phenotype was not captured when the cells were grown on plastic Petri dishes, a standard method used to culture the cells in vitro. This highlights the importance of considering the mechanosignals a cell receives when growing in its native environment. We also verified these findings in-vivo using GBM mouse models. We showed that the recurrent cells could remodel their microenvironment such that the mice’s brains became stiffer, thus promoting the aggressiveness of cancer. This model system was also able to recapitulate clinical trial results of the afatinib drug, where the patient survival outcome was not affected significantly. However, using our model system, we identified a protein, PLEKHA7, that was significantly upregulated in recurrent cells grown on 0.5kPa and was also found to be high in recurrent GBM patient biopsies. PLEKHA7 knockdown reduced the invasion and survival of recurrent GBM cells, suggesting that it could be a potential target for recurrent GBM.