Glioblastomas kill approximately 22,000 people each year, and conventional therapies such as surgery, chemotherapy, and radiation are largely ineffective in extending patient survival past 18 months. One feature of GBMs that makes them so deadly is their ability to diffusely invade throughout the brain parenchyma, thus making complete surgical resection impossible. By better understanding the mechanisms by which GBM cells migrate and invade throughout the brain, it may be possible to find new therapeutic targets to stop this invasive process. ? The long-term goal of this project is to determine the role of N-cadherin post-translational processing in ? promoting glioblastoma invasion. N-cadherin is a cell surface protein that promotes the invasion of many tumor types, but its role in glioblastomas has not been fully characterized. By studying the regulation and function of N-cadherin, a protein known to promote cell invasion in other tumors, new therapeutic targets for GBMs may emerge. This project is therefore translational in nature, and supports the mission of the NCI (NIH) to find a cure for tumors.
In aim #1, the regulation of N-cadherin post-translational cleavage will be characterized. Pharmacological inhibitors and siRNA will be used to silence expression of proteins thought to regulate N-cadherin processing (i.e. protein kinase C and matrix metalloproteinases). The rationale is that by determining the proteins that regulate N-cadherin, we will gain a better understanding of the pathways that lead to GBM invasion.
In aim #2, the role of N-cadherin post-translational cleavage in promoting tumor cell migration and invasion will be characterized. N-cadherin cleavage will first be reduced via silencing of the regulators identified in Aim #1. N-cadherin cleavage will then be induced by transfecting cells with wild-type N-cadherin or mutant N-cadherin that cannot be cleaved, and the effects on GBM cell migration and invasion will be determined. This will directly test for the role of N-cadherin in GBM migration/invasion.
Glioblastomas are highly aggressive brain tumors that are associated with a very poor prognosis, primarily because they are able to invade extensively throughout normal brain tissue. This invasion tends to make the tumors very difficult to remove with surgery. This study will investigate the function of one protein that may be responsible for promoting tumor invasion, with the hopes of better understanding how to stop glioblastomas from progressing. ? ? ?
| Kohutek, Zachary A; diPierro, Charles G; Redpath, Gerard T et al. (2009) ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration. J Neurosci 29:4605-15 |
