The conversion of polarized epithelial cells to non-polarized migratory mesenchymal cells occurs during the normal development of organs and tissues. This process, termed epithelial to mesenchymal transition (EMT) underlies many cell movements during development. During the development and spread of many tumors, tumor cells acquire an invasive capacity and ability to migrate long distances (metastasize). The transformation of benign (non-invasive and non-metastatic) tumor cells to malignant (invasive and metastatic) has many of the hallmarks of EMT. Understanding the regulators of EMT may lead to potential therapies to combat tumor invasiveness and long distance spread during the development of many cancers. Glioblastoma multiforme (GBM) is characterized by its highly invasive and migratory nature, and how GBM cells initiate their movements away from a central tumor core remains poorly understood. Recent studies implicating cells with stem cell characteristics in initiating and maintaining GBM suggest that greater understanding of how normal neural stem/progenitor cells initiate migration may provide novel insights for brain tumor development. During the normal development of the mammalian cerebral cortex, neural progenitor cells undergo an epithelial to mesenchymal transition, changing from highly polarized neuroepithelial cells to multipolar migratory neural progenitors and neurons. Our preliminary work suggests that in vivo knockdown of the adherens junction component N-cadherin leads to cell-autonomous, premature migration from the ventricular neuroepithelium (initiation of EMT). While these studies suggest that disassembly of adherens junction components can initiate EMT in normal neural precursors, mechanistically, how adherens junction loss leads to migration are poorly understood. Our preliminary data suggest the unexpected finding that the initial events of EMT may require transient reduction of AKT and ?-catenin signaling. Here we propose experiments to examine the relationships between N-cadherin, AKT, and ?-catenin signaling in normal neural development and glioblastoma, and to utilize in utero gene delivery approaches to perform focal gain and loss of function experiments in an otherwise normal tissue background to examine the initiation of the epithelial-mesenchymal transition of mammalian cortical neural precursors. Specifically, the studies we propose aim to examine the hypothesis that N-cadherin regulates AKT signaling in cortical neural precursors to initiate the epithelial to mesenchymal transition. These studies will provide additional insights onto mechanisms regulating the initiation of cell migration and may lead to the identification of novel therapeutic targets in brain cancers.
Malignant brain tumors are characterized by a core central mass and peripheral cells that migrate away from the core and invade surrounding tissue. Understanding how cells initiate movement may lend insight onto potential treatments for brain tumors. The goals of this proposal are to elucidate the mechanisms by which tumor cells initiate movements by studying how normal neural stem and precursor cells transition to mobile cells during development.
| Zhang, Jianing; Shemezis, Julie R; McQuinn, Erin R et al. (2013) AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development. Neural Dev 8:7 |
| Schulte, Jessica D; Srikanth, Maya; Das, Sunit et al. (2013) Cadherin-11 regulates motility in normal cortical neural precursors and glioblastoma. PLoS One 8:e70962 |
