gms | German Medical Science

70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

Microenvironmental release of CHI3L1 drives transcriptional re-programming and promotes proliferation

Freisetzung von CHI3L1 aus der Mikroumgebung von Glioblastomen fördert die transkriptionelle Umprogrammierung und Proliferation

Meeting Abstract

  • presenting/speaker Julian Wurm - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland
  • Simon Behringer - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland
  • Pamela Franco - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland
  • Jürgen Beck - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland
  • Oliver Schnell - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland
  • Dieter Henrik Heiland - Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocP077

doi: 10.3205/19dgnc415, urn:nbn:de:0183-19dgnc4154

Veröffentlicht: 8. Mai 2019

© 2019 Wurm et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Reactive astrocytes constitute a major component of the cellular environment in glioblastoma, although their function and crosstalk to other components of the environment is still poorly understood. In a recent work, we identified CHI3L1, a cytokine which is related to inflammation, extracellular tissue remodeling and fibrosis, as exclusively released by tumor-associated astrocytes. Therefore, the following study aimed to subsequently examine the impact of CHI3L1 on tumor malignancy.

Methods: Astrocytes from glioblastoma and non-malignant cortex specimens were purified by immunoprecipitation and gene expression of CHI3L1 was analyzed by quantitative PCR. Results were validated in a co-culture model of tumor cells and astrocytes by RNA-sequencing and large-scale cytokine profiling. Co-Immunoprecipitation was performed to identify CHI3L1 protein-protein interaction. CHI3L1 stimulation of tumor cells was performed to identify downstream pathway activation on protein and transcriptome levels. A human organotypic slice model was used to quantify malignant properties such as invasiveness and migration of the tumors after CHI3L1 stimulation with and without gene knockdown of the identified CD213A2 receptor respectively

Results: Gene expression analysis of purified astrocytes of tumor and non-infiltrated cortex showed a significant up-regulation of CHI3L1 within tumor regions. Additionally, we detected an increased level of extracellular CHI3L1 after astrocytic-tumor co-culture and a significant up-regulation of CHI3L1 gene expression in co-cultured astrocytes, suggesting that CHI3L1 was predominantly released by tumor-associated astrocytes. A co-immunoprecipitation identified CD213A2 as the target receptor of CHI3L1 on tumor cells. Stimulation of tumor cells with CHI3L1 resulted in a MAPK and AKT pathway activation on protein and transcriptional levels. We showed in a brain slice model that CHI3L1 stimulation drives malignant transformation, invasiveness and proliferation.

Conclusion: These findings show a distinct role of CHI3L1 supporting the increase of tumor growth and malignancy. CHI3L1 is released by tumor-associated astrocytes and drives MAPK/AKT activation mediated by CD213A2 in tumor cells. This novel microenvironmental crosstalk opens up new prospectives for targeted therapies in glioblastoma.