TMOD-09DISTINCT TUMOR PHENOTYPES FROM NEURAL PROGENITOR CELL-DERIVED TUMORS

Abstract

Glioblastoma (GBM) is a heterogeneous disease and can exhibit a diversity of cell behaviors and responses to therapy, even when driven by a similar set of oncogenic alterations. Using a murine model for glioma based on the genetic manipulation of neural progenitor cells, we asked whether heterogeneous tumors with different tumor cell behaviors and malignancy could be generated using the same oncogenic driver. We established two tumor progenitor cell (TPC) clones with different survival, an aggressive line with short survival (TPC-S) and a less aggressive line with longer survival (TPC-L). Both TPC clones formed invasive tumors in vivo, however with distinct invasive features. TPC-S cells invaded as cohesive clusters, whereas TPC-L cells invaded diffusely, as single cells. Gene expression analysis, proliferation assays, flow cytometry, and cell differentiation assays, were used to define these two cell populations. Aggressive TPC-S cells expanded at almost twice the rate of TPC-L cells in vitro and were enriched for genes associated with DNA proliferation. TPC-S cells had high expression of neural stem/progenitor cell markers, including Prom1 and Id1 compared to TPC-L. Interestingly, the two lines exhibited differences in differentiation capacity with TPC-S cells unable to differentiate in vitro, while TPC-L cells readily formed both Tuj1 and GFAP expressing cells. In the current project we demonstrate how cells with the same oncogenic driver can give rise to tumors with vastly different properties, reflective of different GBM phenotypes. These lines are being used to examine tumor heterogeneity in both mechanistic and preclinical studies.