Artikel
Metabotropic glutamate receptor III inhibition sensitises GBM to chemotherapeutics
Die Hemmung des metabotropen Glutamatrezeptors III sensibilisiert GBM für Chemotherapeutika
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Veröffentlicht: | 25. Mai 2022 |
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Gliederung
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Objective: Novel insights into the developmental trajectory exhibited by glioblastoma (GBM) have revealed that GBM responds to alterations in the microenvironment by clonal selection of specific phenotypes. Using similar mechanisms, malignant GBM develop intrinsic resistance to chemotherapeutics. Although glutamate signaling has been reported to sustain malignancy, the extent to which metabotropic glutamatergic signaling modulates the GBM landscape remains unknown. In this study we addressed the clinical relevance of Glutamate Metabotropic Receptor III (mGlur3) receptor expression in GBM and provide a proof of concept where we manipulate intrinsic mechanisms of chemoresistance, driving GBM towards chemo-sensitization through mGlur3 receptor inhibition.
Methods: Patient derived samples were quantified for expression of mGlur3 by means of immunohistochemistry. Transcriptional characterization of primary glioblastoma cell lines was carried out to determine expression of mGlur3. Primary GBM cell lines were treated with TMZ and a combination of TMZ and a specific inhibitor of mGlur3 (LY341495) for transcriptomic characterization. Finally, human organotypic tissue sections inoculated with GBM cells were treated with the combination and tumor growth and proliferation were optically quantified for a period of 10 days.
Results: Exploration of patient samples revealed an increased expression of mGlur3 in recurrent GBM (N=?12, p?<?0.0001). Transcriptional characterization revealed that the inhibition of mGlur3 results in loss of axonogenesis (FDR<0.01) and general network building features. Additionally, treatment with a combined regimen resulted in alterations in the transcriptional profile of chemo resistant GBM, with a switch to mesenchymal like phenotype (FDR<0.01), allowing cytotoxic targeting by temozolomide. A significant reduction in GBM growth and proliferation was observed ex-vivo when mGlur3 inhibition was combined with temozolomide therapy (N=?3, p?<?0.0001).
Conclusion: Through the integration of diversified molecular-biological analyses and sequencing data analysis we present a new concept, where we not only illustrate mechanisms of resistance, but rather a mechanistic understanding of how glutamate signaling via mGluR3 interacts with the phenotypical GBM landscape formation in the light of recently published GBM cell-state discoveries.