ATPS-34THE ROLE OF Lrig1 AND Lrig3 IN PDGF-INDUCED EXPERIMENTAL GLIOMA

Abstract

In both adult glioblastoma (GBM) and pediatric diffuse intrinsic pontine glioma (DIPG) dysregulated platelet-derived growth factor (PDGF) receptor (PDGFR) signaling is a common feature. The majority of GBMs of the pro-neural subtype and many DIPGs have activating mutations, or amplifications, of PDGFRA gene and it was recently suggested that PDGFA drives the initiation of all non-CIMP GBMs. Leucine-rich repeats and immunoglobulin-like domains (Lrig) -1 is a negative regulator of PDGFRA and a tumor suppressor in the mouse intestines. The functions of Lrig2 and Lrig3 are less well defined. However, recently we showed that Lrig2-deficient mice are protected against PDGF-induced glioma. The roles of Lrig1 and Lrig3 in PDGF-induced glioma have not been addressed, previously. In the present study, brain tumors were induced in Ntv-a transgenic mice of different Lrig1 and Lrig3 genotypes by intracranial injection with PDGFB-encoding RCAS-producing DF-1 cells. Lrig1-deficient mice developed more tumors than wild-type mice (36%, n = 44 vs. 22%, n = 36). Furthermore, Lrig1-deficient mice developed more high grade tumors than the corresponding wild-type mice (11% vs. 2%). Lrig3-deficient mice, in contrast, developed fewer tumors than the corresponding wild-type mice (64%, n = 26 vs. 77%, n = 30). Additionally, Lrig3-deficient mice developed no tumor of high grade, whereas 13% of the corresponding wild-type mice developed high grade tumors. In situ hybridization analysis revealed Lrig3 expression within the induced wild-type tumors; Lrig1 expression has not been analyzed, yet. Thus, this study revealed an apparent glioma-protective function of Lrig1, and an apparent glioma-promoting function of Lrig3, in PDGFB-induced glioma. These results suggest that Lrig1 and Lrig3 might have opposing functions in gliomagenesis.