Developmental Origins of Aggressive Medulloblastoma

Abstract

Medulloblastomas represent a heterogeneous group of cerebellar tumors that constitute the most frequent primary pediatric solid malignancy. Molecular characterization of these tumors have led to the understanding that distinctsubtypes possess characteristic properties such as gene expression profile, histological classification, and degree of dissemination that are predictive of disease progression and prognosis. Fractionation of primary medulloblastomas has led to the appreciation of brain tumor stem cells (BTSC) that may be driving the more aggressive and malignant disease. However, the developmental origins of these cells as well as the influences of early mutations in tumor suppressors on development and tumorigenesisremain unclear. My work is geared towards understanding the impact of mutations in the key tumor suppressor genes Ptc1 and p53 on medulloblastoma formation. I first identified key differences in neural stem cell marker expression that distinguish between Ptc1 and Ptc1;p53 medulloblastomas, demonstrating that the Ptc1;p53 genotype may pre-dispose to a more malignant, stem-like tumor. Through the use of a somatic mosaic model, we describe a synergistic interaction between Ptc1 haploinsufficiency and p53 deficiency leading to developmental seeding of the cerebellar field by pre-malignant cells and term this phenomenon “developmental field cancerization.” Interestingly, we observed this premalignant colonization in the cerebellarstem cell compartment as well, resulting in an aberrant population of self-renewing cells. Upon loss-of-heterozygosity at the Ptc1 locus, the Ptc;p53 animals alone develop robust cerebellar tumorsthat possess a definable stem-like population of cells that can re-initiate metastatic secondary tumors. These findings demonstrate how early mutationsin the tumor suppressor genes, such as Ptc1 and p53, may lead to stem cell field cancerization and play an important role in determining future tumor character and prognosis.