Abstract 106: Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells

Abstract

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. We and other groups have identified mutation-harboring neural stem cells (NSCs) in the subventricular zone (SVZ) as cells-of-origin carrying driver mutations (Lee et al, Nature 2018). However, little is known about the evolutional process by which mutation-harboring NSCs in the SVZ transform into distant cancer cells with a high degree of molecular heterogeneity. Here, using a spontaneous, somatic mouse model that recapitulates human GBM arising from NSCs that carry driver mutations, we show that mutation-harboring NSCs transform into precancerous cells through oligodendrocyte progenitor cell (OPC) lineage specification during tumor evolution. These precancerous cells show dysregulated translation and/or modification of extracellular matrix (ECM) prior to tumor formation. They subsequently give rise to GBMs with intratumoral heterogeneity exhibiting multiple developmental cell states as in human GBM, and also show activation of additional transcriptional programs, including immune evasion, ECM remodeling, epithelial-mesenchymal transition, and proliferation. Importantly, we further identified precancerous cell populations carrying driver mutations, namely gain of chromosome 7 and loss of chromosome 10 in tumor-free SVZ tissues from GBM patients with intratumoral heterogeneity. These human precancerous cells indeed exhibited OPC and neural progenitor cell-like expression patterns similar to those in our spontaneous GBM mouse model. Thus, our results demonstrate that cell-type specification of precancerous cells with oncogenic transcriptional programs underlie evolution of GBM from mutation-harboring NSCs and intratumoral heterogeneity. Citation Format: Jeong Ho Lee, Hyun Jung Kim, Seok-Gu Kang. Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 106.