University thesis:
Dissertation, Universität Freiburg, 2024
Footnote:
Description:
Abstract: Glioblastomas are the most devastating malignant brain tumor and the most common cancer of the central nervous system. The structural immunity of the brain, namely microglia and astrocytes, are of paramount importance to drive tumor differentiation and heterogeneity resulting in the malignant nature of glioblastoma. Here, the interplay between tumor-associated astrocytes and glioblastoma was investigated by highlighting the role of the protein chitinase 3 like protein 1 (CHI3L1). Gene expression mapping of astrocytes from tumor-, and non malignant brain samples revealed a reactive transformation of astrocytes along with significant upregulation of CHI3L1. These findings were confirmed across a large cohort on expression and protein level suggesting that the impact of CHI3L1 may contribute to the malignant character of glioblastoma. To further investigate the underlying molecular mechanism, a co-culture model was established which confirmed astrocytes as the origin of CHI3L1 release. Primary glioblastoma cells revealed a transcriptional subtype switch towards the mesenchymal gene expression subgroups which was linked to worse outcome in patients. Various stimulation experiments confirmed that this effect was based on the impact of CHI3L1 in the tumor microenvironment. Gene expression analysis and protein mapping confirmed that CHI3L1 stimulation leads to a MAPK and AKT activation in glioblastoma cells which was recently described as the major driver of the mesenchymal subgroup. Computational modeling identified receptor interleukin 13 receptor alpha 2 as the most likely binding partner which was confirmed by co-immunoprecipitation. Downstream inhibition of the MAPK pathway was able to rescue the impact of CHI3L1 on cell proliferation suggesting that the identified mechanism contribute to the malignant nature of glioblastoma. The presented data highlighted a novel role of reactive astrocytes in the tumor microenvironment and provide future perspectives of targets for glioblastoma treatment