Claudia Petritsch, Ph.D., The Regents of the University of California
Funding duration 2012-2014, Program Summary
Studies have shown that a mutant activated form of BRAF, BRAFV600E, and concomitant homozygous deletion of CDKN2A occur in a subset of pediatric malignant astrocytomas. Importantly, BRAFV600E transforms CDKN2A-deficient neural progenitor cells and BRAF kinase is involved in signaling pathways that decide whether neuronal cells undergo differentiation vs. sustained self-renewal. Self-renewal and differentiation in the progeny of neural stem cells (NSC) and oligodendrocyte progenitor cells (OPC) is controlled by their ability to exhibit polarized intracellular localization of cell fate determinants and unequally segregating them between their daughter cells. This type of division is very fundamental and frequent and is called an asymmetric division. Our recent data suggest that de-regulation of asymmetric division occurs in glioma stem and glioma precursor cells and it contributes to their ability to maintain tumor growth.
Our objective here is to determine if BRAFV600E expression affects asymmetric cell division in a developmental and cell-type specific manner and if this disruption is important for the transforming ability of BRAFV600E and its ability to generate heterogeneous malignant astrocytomas (MA). Pharmacological inhibitors of BRAFVE have shown promising anti-tumor effects in melanoma patients and more recently in MA xenografts. In melanoma, treatment resistance rapidly develops to targeted therapy for BRAFVE and the mechanisms for the acquired resistance are only partially understood. Our studies are further aimed in defining changes resulting from targeted therapy, in particular those in asymmetric division, in tumor populations with stem and progenitor like features.
In summary, our studies will unravel if defects in asymmetric divisions are critical for tumor formation in response to BRAFVE expression and in doing so we expect to define points of disruption to which novel MA therapies can be targeted. Funding from the Childhood Brain Tumor Foundation was critical to get the lab started on this project and to establish collaborations crucial for the success of this study.