The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma
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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.
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Dexamethasone blunts the SASP in models of senescent cancer cells.
“Dexamethasone is an approved glucocorticoid (Dexamethasone in Hospitalized Patients with Covid‐19—Preliminary Report, 2020) and has been demonstrated to blunt the SASP, albeit in models of senescent cancer cells (Ge et al, 2018; Buhl et al, 2019).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Buhl et al, 2019
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- Authors
- Buhl, J. L., Selt, F., Hielscher, T., Guiho, R., Ecker, J., Sahm, F., Ridinger, J., Riehl, D., Usta, D., Ismer, B., Sommerkamp, A. C., Martinez-Barbera, J. P., Wefers, A. K., Remke, M., Picard, D., Pusch, S., Gronych, J., Oehme, I., van Tilburg, C. M., Kool, M., Kuhn, D., Capper, D., von Deimling, A., Schuhmann, M. U., Herold-Mende, C., Korshunov, A., Brummer, T., Pfister, S. M., Jones, D. T. W., Witt, O., & Milde, T.
- Affiliations
- German Cancer Research Center (DE)
- University College London (GB)
- 6Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK.
- 1Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
- 7Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
- Universitätsklinikum Tübingen (DE)
- 18Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
- University of Freiburg (DE)
- Corresponding author
- Milde, Till
- ORCID
- Buhl, Juliane L.
- Selt, Florian
- Hielscher, Thomas
- Guiho, Romain
- Sahm, Felix
- Ridinger, Johannes
- Usta, Diren
- Wefers, Annika K.
- Remke, Marc
- Picard, Daniel
- Pusch, Stefan
- Gronych, Jan
- Oehme, Ina
- Kool, Marcel
- Capper, David
- Schuhmann, Martin U.
- Korshunov, Andrey
- Brummer, Tilman
- Pfister, Stefan M.
- Jones, David T.W.
- Witt, Olaf
- Milde, Till
- Venue
- Clinical Cancer Research
- Published
- 2019-03-15
- Volume
- 25
- Issue
- 6
- Pages
- 1851-1866
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2903690341
- Cited by
- 84
- References
- 57
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 18 · 2023: 11 · 2022: 14 · 2021: 11 · 2020: 10 · 2019: 3
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- German Research Foundation (Oe542/2-1)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- pilocytic astrocytoma, senescence-associated secretory phenotype, oncogene-induced senescence, MAPK signaling, IL-1β, interleukin-6, dexamethasone, tumor progression prediction, pediatric brain tumors, tumor growth arrest
- MeSH terms
- Progression-Free Survival, Animals, Astrocytoma, Brain Neoplasms, Child, Disease Models, Animal, Female, Humans, Male, Prognosis, Tumor Cells, Cultured, Cellular Senescence, Culture Media, Conditioned, Gene Expression Profiling, Cell Proliferation, Mice, Interleukin-1beta, Primary Cell Culture, Datasets as Topic
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