The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma.

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The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma.

Clin Cancer Res. 2018 Dec 07;:

Authors: Buhl JL, Selt F, Hielscher T, Guiho R, Ecker J, Sahm F, Ridinger J, Riehl D, Usta D, Ismer B, Sommerkamp AC, Martinez-Babera JP, Wefers AK, Remke M, Picard D, Pusch S, Gronych J, Oehme I, van Tilburg CM, Kool M, Kuhn D, Capper D, von Deimling A, Schuhmann M, Herold-Mende C, Korshunov A, Brummer T, Pfister SM, Jones DTW, Witt O, Milde T

Abstract
PURPOSE: Pilocytic astrocytoma (PA) 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 PAs. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in PA remains unknown.
EXPERIMENTAL DESIGN: The patient-derived PA cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in PA. 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 PA tumors were analyzed by GEP and multiplex assay.
RESULTS: SASP factors were up-regulated in primary human and murine PA and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating PA cells. The SASP factors IL1B and IL6 were up-regulated in primary PA, 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 pan-BCL inhibitors. High IL1B and SASP expression in PA tumors was associated with favorable progression-free survival.
CONCLUSIONS: We provide evidence for the SASP regulating OIS in pediatric PA, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in PA patients. Further investigation of the SASP driving the unpredictable growth of PAs, and its possible therapeutic application, is warranted.

PMID: 30530705 [PubMed - as supplied by publisher]

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