The Functions of Rictor, Pten and p53 Signaling Pathways in Brain Tumors and Brain Development.

Abstract

Glioblastoma is the most common malignant neoplasm of the central nervous system. Despite intense treatment plans and supportive care, the median survival rate remains approximately 12-15 months. Comprehensive analyses have demonstrated that approximately 90% of glioblastomas have elevated PI3K/AKT signaling accompanied by chromosome-10 (chr10) loss. We, therefore, investigated the clinical implications of genetically inhibiting Rictor/mTORC2, a positive regulator of the PI3K/AKT pathway. We show that mutant-p53 driven mouse gliomas undergo independent but concurrent loss of chr19 and chr7, syntenic to human chr10q, which results in Pten deletion and hyperactivation of PI3K/Akt. Removal of Rictor, and by extension PI3K/Akt signaling, exerts significant tumor suppressive activity in both initiation and progression of high-grade gliomas. However, this oncogenic pathway is not absolutely required for a group of gliomas, calling for a need to identify the other molecular events that may lead to tumor resistance and recurrence.

Unpredictably, embryonic inactivation of Rictor/mTORC2 increases the frequency of mutant-p53 driven medulloblastoma development. In contrast to glioblastoma, which is mostly associated with adult oncology cases, medulloblastoma is largely a pediatric malignancy of the cerebellum affecting infants and children. Our analyses suggest that Rictor loss delays the cell cycle exit and neuronal differentiation in a subset of cerebellar progenitors leading to an increased predisposition to mutant-p53 induced medulloblastoma formation. These tumors exhibit distinctive genomic alterations that are associated with poor clinical outcome, providing a platform to study alternative treatment options for incurable kids.

Given the cell type-specific roles of Rictor/mTORC2/Akt signaling in brain tumorigenesis, our additional analyses aimed to understand its roles in different neuronal populations during the brain development. We show that intact Pten functions, including the regulation of PI3K/Akt signaling, are required for the proper neuronal layering, and the generation and/or survival of a subset of projection neurons in the cerebral cortex. These findings provide valuable insight into cognitive and neurodevelopmental defects observed in patients with germline PTEN mutations.

Together, this thesis work identifies Rictor/mTORC2 as a signaling pathway with opposing roles in adult and pediatric brain tumors, and uncovers novel roles for Pten in the formation of neuronal architecture during the brain development.