Tumor Suppressor p53 in Cerebellar Development, Medulloblastoma Initiation, and Treatment Resistance.

TP53 is a crucial tumor suppressor inactivated in the majority of human cancers. Medulloblastoma (MB), the most common malignant pediatric brain tumor, is an exception, rarely mutating TP53. Within the Sonic Hedgehog (SHH) MB subtype, TP53 mutation is a prognostic factor, and mutant TP53 SHH-MBs have the worst prognosis of all subtypes. How most SHH-MBs can form without mutating TP53 remains unclear. Almost all SHH-MBs with TP53 mutation arise during childhood, indicating that mutation to TP53 must occur during a limited developmental window. Early postnatal (postnatal day 0.5) granule cell precursors (GCPs) are p53-activation resistant following genotoxic stress, whereas late postnatal (postnatal day 10) GCPs are p53-activation sensitive. I hypothesize that a p53-activation resistant GCP population gives rise to p53 wild type SHH-MBs and that p53-activation sensitive GCPs are eliminated during postnatal development unless they harbor mutant p53. Using two mutant p53 alleles, a conditional knockout, p53∆E5-6, and a hypomorph, p53R172P, I demonstrated that p53 activation occurs during cerebellar development, and is activated in the earliest detectable lesions driven by Ptch1 loss. Consistently, p53-dependent apoptosis plays a major role in both the initiation and progression of SHH-MBs, while p53-dependent cell cycle arrest only delays SHH-MB progression. Surprisingly, a subset of Ptch1-deficient pre-neoplastic lesions (PNLs) showed no evidence of p53 activation, regardless of p53 mutation, providing a mechanistic basis for the formation of p53 wild type (WT) SHH-MBs. To test whether these PNL represented a p53-activation resistant population, I designed a clinically relevant treatment scheme to induce genotoxic stress and elicit a heightened p53 response. I found that treatment eliminated all PNL cells and reduced the incidence of SHH-MBs, but only when p53-mediated apoptosis was activated. Activation of p53-mediated cell-cycle arrest alone halted proliferation and induced neuronal differentiation, but failed to eliminate Sox2-positive stem-like cells, which were capable of surviving treatment and generating highly proliferative SHH-MB. Thus, only when p53 activation surpasses a critical threshold will Sox2-positive stem-like cells be eliminated, preventing p53 recurrence and determining therapeutic outcomes.PHDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135886/1/treisman_1.pd