Medulloblastoma is known to be the most malignant pediatric brain tumor. The armamentarium of targeted therapies to currently treat medulloblastoma and similar pediatric central nervous system malignancies is extremely limited, often necessitating the need to combat such tumors with modified regimens of therapeutic options designed originally to target adult neoplasms. Given such limited therapies, a budding focus on the role of mitochondrial dysregulation in the tumorigenesis of such pathologies merits consideration. Mitochondria are known to play fundamental roles in multiple processes conserved across eukaryotic species. Aside from their key role in energy production through oxidative phosphorylation, the organelles also serve as the sites of essential metabolic pathways, redox regulation, calcium homeostasis, apoptosis, and cell fate determination and differentiation.

Recently, we documented the role of noncanonical Notch signaling and mitochondrial involvement in adult glioblastoma brain tumor-initiating cells (Lee KS et al., Genes and Development, 2013). Although the canonical Notch pathway and is generally well-characterized, involving the ligand-induced cleavage of Notch for transcriptional regulation, only more recently has credible evidence surfaced documenting the role of a second noncanonical pathway, where Notch can function independently of ligand and transcription through a mechanism that remains to be fully elucidated. The regulatory self-renewal versus differentiation choice of Drosophila and mammalian human neural stem cells requires Notch signaling, and in our work, we found noncanonical Notch pathway interaction with PTEN-induced putative kinase 1 (PINK1) to influence mitochondrial function, activating mTORC2/Akt signaling. siRNA-induced knockdown preferentially impaired the maintenance of Drosophila and human glioblastoma cancer stem cell-like tumor-forming cells to a far greater degree than normal stem cell counterparts.

Further experiments have elucidated similar findings of increased Notch1/PINK1 mitochondrial interaction and mTORC2/Akt activity in patient-derived Group 3 (myc-amplified) medulloblastoma primary lines to levels greater than normal or glioblastoma samples. Additionally these medulloblastoma samples appear to be more susceptible to siRNA-induced knockdown of PINK1 than their counterparts. In vivo experiments are ongoing to address the role of mitochondrial Notch1/Pink1 interaction in tumor initiation and its targeting by small molecule inhibitors. Such results underscore the importance of mitochondria in both normal and cancer stem cell biology, a highly conserved mechanism across species, with exciting implications for the treatment of pediatric central nervous system malignancies.

Citation Format: Abdullah H. Feroze, Kyu-Sun Lee, Sharareh Gholamin, Zhihao Wu, Irving Weissman, Bingwei Lu, Siddhartha S. Mitra, Samuel Cheshier. mTORC2/Akt signaling is modulated by noncanonical mitochondrial Notch1/PINK1 interaction in myc-amplified medulloblastoma tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-207. doi:10.1158/1538-7445.AM2014-LB-207