PM-22 * GENETICALLY ENGINEERED MOUSE MODELS OF CHOROID PLEXUS TUMORS

Abstract

Choroid plexus tumors are the most common brain tumors in children under one year of age, accounting for up to 20% of brain tumors in that age group. These tumors exhibit a range of malignancies, from relatively benign choroid plexus papillomas (CPPs) to extremely aggressive choroid plexus carcinomas (CPCs), which despite intensive therapy, have a dismal prognosis. More effective treatments for these tumors depend on animal models that can be used to study tumor biology. We have created animal models of choroid plexus tumors by crossing mice carrying Cre-inducible alleles of Myc (LSL-MycT58A) and Cre-deletable alleles of p53 (p53flox) to animals that express Cre recombinase in neural stem cells or progenitors (Atoh1-Cre or Blbp-Cre). The progeny of these crosses develop choroid plexus tumors with high penetrance: activation of Myc alone results in CPPs, and concomitant deletion of p53 accelerates tumor growth and malignancy, culminating in formation of CPCs. Histological analysis indicates that mouse CPPs and CPCs resemble their human counterparts, and that CPCs (but not CPPs) exhibit reduced expression of normal choroid plexus epithelial markers and loss of tight junction proteins. Gene expression profiling reveals that CPPs and CPCs have altered expression of cell cycle regulators, and exhibit hallmarks of genomic instability and DNA damage responses. CPCs, but not CPPs, also exhibit abnormal telomere function and have increased expression of stem cell markers and hypoxia-induced genes. These studies provide important insight into the mechanisms of choroid plexus tumorigenesis, and yield valuable animal models that can be used to identify novel therapies for patients with aggressive choroid plexus tumors.