Abstract IA005: Shaping tumor cell plasticity and therapy resistance in glioblastoma

Abstract Tumor heterogeneity fueled by plasticity and genetic diversification of cancer cells is key to therapy failure of malignant glioma. We implemented spatial and genetic platforms at single cell resolution to explore the trajectory of evolution of glioblastoma. Using spatial analysis of whole glioblastoma sections, we established a homotypic clustered cell identity paradigm whereby tumor cell state coherence was maximal in cells organized in homotypic clusters, whereas dispersed cells downregulated the original state, acquired alternative phenotypes and exhibited changes in the microenvironment, thus linking the process of plasticity to loss of the cell adhesion mechanisms that preserve the clustered spatial pattern of glioblastoma cells. We also used single cell DNA-sequencing methods integrated with the single cell transcriptome of patient-matched primary-recurrent glioblastoma pairs to resolve the clonal substructure of untreated glioblastoma and determine the clonal evolution at recurrence driven by therapeutic resistance. The evolutionary trajectory of glioblastoma identified a bottleneck model as the predominant pattern of evolution and converged on the identification of a rare persister subclonal state in primary glioblastoma exhibiting distinct phenotypic hallmarks that evolves and diversifies to populate the recurrent tumor mass. We used preclinical tumor models to trace the individual lineages associated with the persister subclones and experimentally illuminated the biological and metabolic activities of the persister cellular state in brain tumors. Persister glioblastoma cells in untreated tumors lacked spatial segregation and were independent predictors of timing to recurrence for glioblastoma patients. Thus, genetic and non-genetic co-evolution mechanisms forge the acquisition of plasticity and therapy resistance in glioblastoma. Citation Format: Antonio Iavarone. Shaping tumor cell plasticity and therapy resistance in glioblastoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr IA005.