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

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.

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