Role of GRP78 and CRTAC1 in Glioma Invasion
Background
Pediatric high-grade gliomas (pHGG) are devastating childhood brain tumors. One characteristic of pHGG is that it invades rapidly into surrounding healthy tissues, rendering surgical resection of the tumor impossible. The lack of surgical options for pHGG contributes to the poor prognosis of the disease; the median survival of patients with pHGGs is 9 months after diagnosis with a 99% 5 year mortality. Despite the fact that diffuse invasion is a defining characteristic of pHGG, the molecular and cellular mechanisms regulating invasion are not well understood.
Project Goal
This project seeks to expand on the Monje lab's discovery that glioma cell growth and invasion is regulated by the brain's activity. Specifically, active neurons secrete proteins that glioma cells may be using to regulate their invasion. Two candidate secreted proteins, CRTAC1 and GRP78, have been identified as putative mediators of glioma invasion. CRTAC1 acts as antagonist of the Nogo receptor and inhibits the Rho-ROCK signaling pathway to promote actin stabilization and motility, potentially contributing to neurite outgrowth and glioma invasion. GRP78 is a protein that has a multitude of cellular functions and has been implicated in the growth of other gliomas as well as the invasive behavior of other cancers through similar down-regulation of the Rho-ROCK pathway. To better understand the role of these proteins in promoting tumor invasion, we will test the hypothesis that brain secretions from CRTAC1 and GRP78 knock-out murine models will result in diminished tumor invasion compared to secretions from their wild-type counterparts. I will collect media surrounding spontaneously active brain slices from CRTAC1 and GRP78 knock-out murine models as well as age-matched wild-type control murine models in order to obtain brain secreted proteins. The contribution of secreted CRTAC1 and GRP78 to glioma invasion will then be measured using a 3D in vitro invasion assay of patient-derived pHGG tumor to visualize the extent of glioma cell invasion upon exposure to the media. The results of this work will elucidate the processes by which the surrounding neural microenvironment drives glioma progression and will contribute to the overall goal of identifying a new set of therapeutic targets to limit glioma spread.
Mentored by Dr. Michelle Monje
Stanford University, Stanford, CA
