Tmod-05. regional astrocyte heterogeneity influences evolution of low-grade glioma during malignant progression

Glioblastoma (GBM) has a dismal median survival of around 15 months. Primary and secondary GBM likely evolve from low-grade precursors, albeit via distinct genetic and kinetic mechanisms. Primary GBM is composed of four transcriptome subtypes with distinct mutations and transcriptomes reminiscent of particular brain cells, suggesting that mutations and cellular origin contribute to GBM heterogeneity. However, the effects of regional heterogeneity among putative cells of origin on GBM pathogenesis remain elusive. We used genetic lineage tracing and fate mapping in conditional, inducible mice to show that inactivating Rb (T) and Pten (P) combined with activating Kras (R) (TRP) mutations transformed two subpopulations of mouse astrocytes expressing Gfap or Glast. While a large, broadly-distributed population of astrocytes were Gfap+ (~50%), Glast astrocytes were less abundant (8-38%) and regionally variable. Transformation of each subpopulation by the same oncogenic TRP mutations produced tumors with distinct growth kinetics. Gfap astrocyte transformation induced low-grade tumors with uniformly rapid growth, clonal expansion (Ki-67 labeling), and progression to lethal, GBM. In contrast, Glast astrocyte transformation induced regionally variable tumors with indolent growth, protracted clonal expansion, and progression to anaplastic, non-GBM gliomas. In addition to growth kinetics, we found that regional astrocyte heterogeneity influenced the genomic profiles of both low- and...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MODELS Source Type: research