Glioblastoma (GBM) represents the majority of diagnosed brain tumors with a high rate of mortality. GBM is a heterogeneous glial tumor found in the adult cerebral cortex. Due to the heterogeneity within the tumor and from patient to patient, treatment is extremely challenging. Many clinicians and researchers believe that targeting the tumor "cell of origin" will be key to providing better outcomes for patients. Whether GBMs arise from a transformed stem cell or a more differentiated cell that has been transformed is hotly debated. Platelet derived growth factor (PDGF) is a molecule that is over expressed and drives tumor growth in the Proneural subclass of GBMs.
I aim to isolate the PDGFR?+ cells that reside in the subventricular zone (SVZ) of transgenic mice by flow cytometry and FACs. I will sort out distinct populations based on an array of cell surface markers identified by previous experiments, CD133/LeX/NG2/PDGFR?/A2B5/EGFR. The cells will be transformed in culture by a deletion of the p53 tumor suppressor and exposure to constitutively expressed PDGF. I will evaluate the tumorigenicity of the different populations of cells along with analyzing the histological and antigenic profile of the different tumors. We hypothesize that there are multiple PDGFR?+ "cells of origin" that can contribute to GBM tumor formation. We also expect variations in tumor susceptibility and the resulting tumors based on the phenotype of the tumor cell of origin. This research will help to answer questions in the cancer biology field that underestimate progenitor cells capacity to form malignant brain tumors. This research is vital to the advancement and understanding of the cancer stem cell hypothesis that is leading cancer research and thought to be associated with untreatable cancers, like GBM. Ultimately if we can identify and characterize the "cell of origin" then we will be better equipped to make drugs that will specifically target the cell that continues to give rise to the tumor, whether it is a stem cel or a progenitor cell.
The project's main goals are to isolate, propagate and characterize the potential tumor forming cells in the central nervous system. This research will be essential in providing further understanding of the cells that initiate aggressive and fatal bran cancers that are resistant to current treatment therapies.
|Moore, Lisamarie; Bain, Jennifer M; Loh, Ji Meng et al. (2014) PDGF-responsive progenitors persist in the subventricular zone across the lifespan. ASN Neuro 6:|
|Bain, Jennifer M; Moore, Lisamarie; Ren, Zhihua et al. (2013) Vascular endothelial growth factors A and C are induced in the SVZ following neonatal hypoxia-ischemia and exert different effects on neonatal glial progenitors. Transl Stroke Res 4:158-70|