ANGI-15. IDH1 R132H MUTATION IMPAIRS GLIOMA INVASIVENESS THROUGH EPIGENETIC REPRESSION OF MMP2 IN EXPERIMENTAL MODELS AND HUMAN GBMS

Abstract Glioblastoma (GBM) is a highly diffusive tumor which restricts the efficacy of surgical resection and facilitates tumor recurrence. Matrix metalloproteinase 2 (MMP2) is the extracellular matrix protease that is activated by MMP14 expressed by microglia and plays a central role in tissue remodeling and tumor progression. The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed in gliomas, results in hypermethylator phenotype and in GBMs is associated with better survival. The impacts of IDH1R132H on the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. We employed unique mouse glioma models which mimic human GBM pathology, coupled with high-dimensional CITEseq and spatial transcriptomics to analyze the immune landscape in different gliomas. Additionally, we performed gelatin zymography, qPCR, wound healing, and DNA methylation qPCR techniques to validate the obtained results. Mmp2 expression and activity varied with IDH1 status in experimental gliomas. Spatial transcriptomics demonstrated that Mmp2 expression is localized within the IDH1 wild-type tumors and absent in IDH1 mutated ones. Gelatin zymography showed the presence of Mmp2 activity in extracts from IDH1 wild-type tumors. Methylation of Mmp2 gene promoter was increased and resulted in decreased Mmp2 expression in IDH1 mutated gliomas. The IDH1 wild-type gliomas showed more diffuse growth patterns (tumors were stained with Nestin antibody) whereas IDH1 mutant gliomas showed more constrained growth patterns. In the TCGA glioma dataset, methylation of the MMP2 gene promoter was increased which was associated with decreased MMP2 expression in IDH1 mutated gliomas. We found that the IDH1 mutation results in hypermethylation of the Mmp2 gene promoter, leading to decreased Mmp2 expression and Mmp2 activity in experimental gliomas and human GBMs. Reduced Mmp2 activity and decreased tumor invasion result in more restricted tumor growth, which may facilitate resection, and radiotherapy, thereby improving patient survival. Studies were supported by National Science Center Poland grant 2020/39/B/NZ4/02683.