DORMIRE · Investigating the mechanisms driving cancer cell DORMancy and REcurrence in glioblastoma

Glioblastoma, the most aggressive primary brain cancer, remains incurable despite combination treatments involving surgery, chemotherapy and radiation, with a median survival of just over 14 months. The host lab recently demonstrated that multiple treatment modalities induce the formation of a fibrotic scar in the brain, a phenomenon observed in both preclinical mouse models and patient samples. This fibrotic scar can serve as a protective niche for dormant glioblastoma cells, supporting their persistence and resistance to therapy. Over time, these dormant cells reawaken, proliferate, invade into the brain parenchyma, and directly contribute to glioblastoma recurrence. Critically, it remains unclear what drives the transition of glioblastoma cells – both into dormancy and subsequently to re-proliferate/recur – within the fibrotic scar. This project aims to uncover the key factors and molecular mechanisms that regulate these switches. To achieve this goal, I will employ two complementary, yet independent strategies: (1) a targeted candidate-driven approach to elucidate the role of specific extracellular/ cancer cell-extrinsic factors enriched in the fibrotic scar in regulating cellular dormancy, using cell and molecular biology techniques; and (2) an in vivo loss-of-function genetic screening approach, aimed at identifying novel cell-intrinsic modulators of dormancy in glioblastoma. Together, these complementary strategies will provide new mechanistic insights into fibrosis-mediated glioblastoma dormancy and escape. Ultimately, this research could identify new molecular targets to inform the development of more effective and durable therapies for glioblastoma.