Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder that results from a mutation in either of two genes, TSC1 or TSC2, that encode the proteins hamartin and tuberin respectively. These proteins normally serve as negative regulators of the mammalian target of rapamycin (mTOR) pathway but upon mutation of one of these genes, patients exhibit hyper-activation of the pathway resulting in significant increases in cell translation, size and proliferation. TSC symptoms include the formation of two types of benign tumors in the brain: subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs). Both of these tumor types present in the ventricular-subventricular zone (V-SVZ) that surrounds the lateral ventricles, but SEGAs are confined to a specific ventral subregion of this neurogenic niche. SENs are typically asymptomatic, but SEGAs can be lethal if left untreated. A critical barrier to research and treatment in the TSC field is that the true cll of origin and the mechanism of SEGA development remain to be elucidated. It is currently unknown why SEGAs present in the ventral V-SVZ and why some individuals develop these tumors while others do not. It is thought that the cells of origin for TSC tumors are the radial gla since they give rise to the stem cells in the adult brain and are the primary progenitors of neurons, glia and oligodendrocytes during development. Recent work on the stem cells within the V-SVZ showed that their location within this niche can predict the type of progeny they will create. Thus, neural stem cells are not a homogenous mix of equivalently plastic cells, but rather are a spatially organized set of restricted and diverse populations. This introduces the idea that certain cell populations are more susceptible to mutations than others and that tumors derived from these cell types may reflect the properties of the location from which they originated. This finding would provide a new avenue for identifying novel therapeutic strategies to treat SEGAs that could also have the potential to treat other tumor types that present with hyperactive mTOR pathway activity. Thus, the focus of this project is to determine how a cell's positional identity contributes to mTOR pathway activity and brain tumor formation. We will use single-cell measurements of mTOR pathway activity, cultured stem cells, and acutely dissected V-SVZ progenitors to dissect the mechanisms driving subregion-specific differences in mTOR pathway activation. We will then investigate how spatially distinct stem cells contribute to the formation of location-specific tumors within the brain using a novel mouse model of the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC). Finally, we will use this mouse model and our single-cell analytical methods to identify non-cell-autonomous effects of mTOR pathway mutations within the V-SVZ.
Patients with Tuberous Sclerosis Complex (TSC) develop two types of benign tumors associated with the stem cell niche in the mature brain - one benign, one life-threatening. The origin of these tumors is not well understood. We hypothesize that specific neural stem cells generate life-threatening tumors, and will test this in the mouse.
| Sinnaeve, Justine; Mobley, Bret C; Ihrie, Rebecca A (2018) Space Invaders: Brain Tumor Exploitation of the Stem Cell Niche. Am J Pathol 188:29-38 |
| Garcia, A Denise R; Han, Young-Goo; Triplett, Jason W et al. (2018) The Elegance of Sonic Hedgehog: Emerging Novel Functions for a Classic Morphogen. J Neurosci 38:9338-9345 |
| Leelatian, Nalin; Doxie, Deon B; Greenplate, Allison R et al. (2017) Single cell analysis of human tissues and solid tumors with mass cytometry. Cytometry B Clin Cytom 92:68-78 |
| Mistry, Akshitkumar M; Dewan, Michael C; White-Dzuro, Gabrielle A et al. (2017) Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum. J Neurooncol 132:341-349 |
| Mistry, Akshitkumar M; Hale, Andrew T; Chambless, Lola B et al. (2017) Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis. J Neurooncol 131:125-133 |
| Yang, Yu-Ping; Ma, Haiting; Starchenko, Alina et al. (2017) A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Rep 19:1257-1267 |
| Leelatian, Nalin; Doxie, Deon B; Greenplate, Allison R et al. (2017) Preparing Viable Single Cells from Human Tissue and Tumors for Cytomic Analysis. Curr Protoc Mol Biol 118:25C.1.1-25C.1.23 |
| Rushing, Gabrielle; Ihrie, Rebecca A (2016) Neural stem cell heterogeneity through time and space in the ventricular-subventricular zone. Front Biol (Beijing) 11:261-284 |
| Leelatian, Nalin; Ihrie, Rebecca A (2016) Head of the Class: OLIG2 and Glioblastoma Phenotype. Cancer Cell 29:613-615 |
