A critical role in glioma malignancy is played by invasion of the tumor cells into local, normal regions of the brain. Because of the limitations on surgery to remove adequate margins to capture these invasive cells, glioma is highly likely to recur after treatment. A better understanding of the mechanisms by which glioma cells invade may enable more effective treatment of glioma. Microglia can enhance glioma invasion, and higher levels of these myeloid cells in gliomas correlates with worse prognosis. A better understanding the mechanisms by which microglia can stimulate glioma invasion could therefore provide new opportunities for treatment. This proposal will address the potential role of the product of the KIF9 gene in microglial stimulation of glioma invasion. The KIF9 gene encodes a kinesin family member and overexpression of KIF9 in gliomas is correlated with shorter survival. Kinesins are associated with movement of cellular components along microtubules. In preliminary studies, we find that suppression of KIF9 reduces microglia-stimulated glioma invasion and secretion of proteases associated with matrix degradation. We therefore hypothesize that KIF9 contributes to glioma invasion through enabling the trafficking of matrix proteolytic enzymes to the plasma membrane for secretion, resulting in enhanced invasive capabilities. The role of KIF9 in invasion will be tested in two specific aims.
In Aim 1, we will evaluate the importance of KIF9 for microglia-stimulated glioma invasion in vitro.
In Aim 2, we will use intracranial injection to test the importance of KIF9 for invasion in vivo. If successful, this grant will establish the value of KIF9 as a potential new target for the development of novel therapeutics.
Invasion of glioma cells is a major contributor to the difficulty in treating glioma. This proposal will study a protein that has not previously been associated with glioma invasion. If successful, the work described in this proposal will identify a new target for the development of novel therapies to attack glioma.