The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma.

Abstract

PURPOSE:

Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of pilocytic astrocytomas. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in pilocytic astrocytoma remains unknown.Experimental Design: The patient-derived pilocytic astrocytoma cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in pilocytic astrocytoma. The model allows for doxycycline-inducible switching between proliferation and OIS. Both states were studied using gene expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary pilocytic astrocytoma tumors were analyzed by GEP and multiplex assay.

RESULTS:

SASP factors were upregulated in primary human and murine pilocytic astrocytoma and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating pilocytic astrocytoma cells. The SASP factors IL1B and IL6 were upregulated in primary pilocytic astrocytoma, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic BCL2 inhibitors. High IL1B and SASP expression in pilocytic astrocytoma tumors was associated with favorable progression-free survival.

CONCLUSIONS:

We provide evidence for the SASP regulating OIS in pediatric pilocytic astrocytoma, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in patients with pilocytic astrocytoma. Further investigation of the SASP driving the unpredictable growth of pilocytic astrocytomas, and its possible therapeutic application, is warranted.

• Authors: Juliane L Buhl, Florian Selt, Thomas Hielscher, Romain Guiho, Jonas Ecker, Felix Sahm, Johannes Ridinger, Dennis Riehl, Diren Usta, Britta Ismer, Alexander C Sommerkamp, J P Martinez-Barbera, Annika K Wefers, Marc Remke, Daniel Picard, Stefan Pusch, Jan Gronych, Ina Oehme, Cornelis M van Tilburg, Marcel Kool, Daniela Kuhn, David Capper, Andreas von Deimling, Martin U Schuhmann, Christel Herold-Mende, Andrey Korshunov, Tilman Brummer, Stefan M Pfister, David T W Jones, Olaf Witt, Till Milde
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 6 Pg. 1851-1866 (03 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30530705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Culture Media, Conditioned
• IL1B protein, human
• Interleukin-1beta

Topics

• Animals
• Astrocytoma (mortality, pathology, surgery)
• Brain Neoplasms (mortality, pathology, surgery)
• Cell Proliferation
• Cellular Senescence
• Child
• Culture Media, Conditioned (metabolism)
• Datasets as Topic
• Disease Models, Animal
• Female
• Gene Expression Profiling
• Humans
• Interleukin-1beta (metabolism)
• Male
• Mice
• Primary Cell Culture
• Prognosis
• Progression-Free Survival
• Tumor Cells, Cultured