Abstract 6926: Tracing clonal evolution and immune evasion in glioblastoma progression

Abstract Glioblastoma continues to be a daunting obstacle in oncology research, with its early-stage progression being particularly enigmatic. In a recent published work, we traced the clonal dynamics of glioblastoma evolution by the simultaneous transfer of PDGFB and genetic barcodes into mouse brains. We observed a continuous clonal loss during the acquisition of a malignant phenotype, underlined by the modulation of the levels of c-Myc expression and their functional targets. In this study, we delve deeper into the evolution of glioblastoma by transplanting multiclonal, early-stage glioma cells into multiple immunodeficient NOD-SCID mice. This experimental design allowed us to track the clonal dynamics over serial transplants, revealing how early-stage glioma clones acquire immune-evasive features capable of initiating tertiary tumors in immune-competent hosts. Through barcode sequencing and single-cell RNA sequencing of early-stage gliomas, coupled with bulk RNA sequencing of secondary and tertiary gliomas, we dissected the clonal and transcriptomic landscape of these tumors. We observed that, of the various clones composing primary tumors, just a few of them are predominating in subsequent passages. Furthermore, the clonal composition of secondary tumors derived from the same primary glioma showed partial overlap, indicating a partial predetermination in the development of immune-evasive behavior. Our intra- and inter-clonal transcriptomic analysis across various stages of tumor progression is shedding light on how new functional traits can emerge in gliomas. Further analysis of our data will determine whether it is the result of the expansion of clones already possessing these traits, or if they stem from functional adaptations within the clones themselves. Our insights further reinforce the concept of clonal competition, highlighting the significant influence of immune-system interactions in driving these competitive dynamics. Citation Format: Davide Ceresa, Sebastian A. Garcia Mena, Francesca Piaggio, Appolloni Irene, Daniela Marubbi, Paolo Malatesta. Tracing clonal evolution and immune evasion in glioblastoma progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6926.