MODL-22. Establishment of a novel system to specifically trace and ablate quiescent/slow cycling cells in high-grade glioma

Abstract

Pediatric and adult high-grade gliomas are the most common malignant brain tumors, with poor prognosis due to recurrence and tumor infiltration after surgical removal and chemotherapy. Quiescent/slow cycling stem cells have been proposed to be one of the main players of tumor relapse but their involvement in in the infiltration remain unclear. Despite they have been described in mouse models or after transcriptional profiling of human tumor samples, their direct visualization, targeting and ablation remains a challenge. Here, we identified a population of malignant cells expressing Prominin-1 in a non-proliferating state in pediatric high-grade glioma patients. We next used a fluorescent cell cycle sensor to visualize quiescence tumor cells in mouse brain cancer and human cancer organoids. In particular, we characterized them within the tumor revealing the invasiveness capacity of slow cycling tumor cells. Furthermore, we generated a new system to specifically trace and ablate such cells. Indeed, lineage tracing experiments allowed to trace quiescent Prom1 progeny in the tumors after temozolomide treatment. In addition, the selective ablation of quiescent Prom1+ cells in mouse brain cancer reduced tumor infiltration and improved survival. Furthermore, time-lapse experiments showed that slow cycling cells are also able to infiltrate co-cultured human brain cancer organoids. Finally, using our new cancer organoid- and GBM spheroids-based models we identified a drug acting on quiescent cells leading to a reduction in cell invasion. Overall, our data show that quiescence/slow cycling cells are key driver of tumor invasiveness, the major malignant feature of high-grade brain cancer.