Inducible astrocytomas in genetically engineered mice: delineation of grade-specific molecular drivers in tractable preclinical models

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-24

* FARE Award Winner

Authors

• Y Song
• Q Zhang
• R Bash
• B Kutlu
• S Difilippantonio
• C Yin
• D Gilbert
• S Wang
• C Yang
• E Bullitt
• T Kafri
• K McCarthy
• D Louis
• L Hood
• C Miller
• T Van Dyke

Abstract

High-grade astrocytomas remain fatal with no effective treatment. Understanding of major regulatory pathways involved in disease etiology will be critical for development of effective diagnoses and therapy. However, few studies have successfully queried cause and effect relationships solely in adult brain using genetically engineered mice (GEM). Here we aimed to develop inducible models of astrocytomas in adult GEM via i.p. 4OH-tamoxifen injection based on common pathways deregulated in human GBM: disruption of pRb function, K-RasG12D activation and Pten inactivation. pRb inactivation alone was sufficient to initiate grade II disease via activation of MAPK through endogenous K-Ras. Further activation of K-RasG12D predisposed to grade III tumors by engaging PI3K/AKT pathway and setting up a selective pressure for Pten loss. With high penetrance and reproducible timing, the combination of all three events predisposed to grade IV tumors (GBM). Sequencing analyses showed that a high fraction of the GEM-GBMs carried spontaneous missense p53 mutations, indicating a selective role in GBM progression. To determine whether tumors resembled any of the molecular subclasses of human GBM, transcriptome analyses were performed and revealed concordance with the highly aggressive human mesenchymal subclass. These models represent a unique resource for further mechanistic analyses and preclinical studies.

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