Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance

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PROJECT ABSTRACT Patients with glioblastoma multiforme (GBM) have poor prognosis and limited treatment options. Immune checkpoint therapies, which have shown dramatic benefits in other cancers, have failed to improve outcomes in GBM patients in all randomized phase III trials. Brain tumors generate mechanical forces as they grow in the confined space of the cranium, and we have shown that these physical forces affect cell viability and phenotype (Nature Biotechnology 1997, PNAS 2012, Nature Biomedical Engineering 2016, 2019, Science 2020). Our preliminary results indicate that compressive forces similar to those in brain tumors are sufficient to upregulate stress granule protein G3BP2 as well as genes associated with epithelial-mesenchymal transition (EMT), stemness and the immune checkpoints. Furthermore, we have shown G3BP2 regulates cancer cell stemness in breast cancer (PNAS 2017). Thus, we hypothesize that mechanical stresses in the GBM environment contribute to GBM stemness and immunosuppression, and that the pathways involved can be targeted to enhance tumor killing. In this project, we will dissect the stress-induced pathways involved in mechanical regulation of stemness and immunosuppression in GBM. We will then block these pathways in orthotopic, immunocompetent mouse models of GBM to enhance immunotherapy. The overall goal of the study is to identify new strategies and targets for amplifying anti-tumor immunity based on mechanobiological control mechanisms.