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 doxycyclineinducible 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.

Response to trametinib treatment in progressive pediatric low-grade glioma patients

“…These could include e.g. the inhibition of other MAPK-related survival pathways like AKT/mTOR [38], or the use of senolytic drugs [37], both of which remain to be introduced into the clinical treatment of pLGGs. PD was observed in 3/11 (27%) of the patients who stopped trametinib, within 4 months after EOT.…”

“…The low rates of CR indicate that parts of the tumor may not be targetable by the MEKi treatment alone, just as is the case with cytotoxic conventional chemotherapy. It is conceivable that this non-responding compartment, possibly quiescent through OIS and SASP [ 15 , 37 ], is the source of the progression observed in some patients after EOT with targeted treatments. Supplementary strategies will therefore be needed to implement additional therapeutic regimens to improve treatment outcome and PFS of these patients.…”

Transient DNMT3L Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast

“…The number of senescent cells in tissues increases with age (Spaulding et al, 1997;Krishnamurthy et al, 2004;Herbig et al, 2006;Krizhanovsky et al, 2008;Vidal et al, 2012;Waaijer et al, 2012), and the rate of their accumulation predicts the lifespan of mice (Jurk et al, 2014). The secretions from senescent cells lead to a senescence-associated secretory phenotype (SASP), which might contribute to aging-associated tissue dysfunction or the development of a cancerous niche in old tissue (Coppe et al, 2010;Castro-Vega et al, 2015;Buhl et al, 2019;Lopes-Paciencia et al, 2019). A recent study showed that the transplantation of senescent cells into mice leads to the early onset of aging-related phenotypes (Xu et al, 2017(Xu et al, , 2018, which supports the current hypothesis that senescence can be a driver of aging (Krtolica et al, 2001;Sturmlechner et al, 2017;Lewis-McDougall et al, 2019).…”

Managing NF2-associated vestibular schwannomas in children and young adults: review of an institutional series regarding effects of surgery and bevacizumab on growth rates, tumor volume, and hearing quality

“…Possible explanations are the pure effect of tumor volume reduction, since we demonstrated that, preoperatively, smaller tumors grew at a slower rate. Secondly, it has been shown in a pilocytic astrocytoma cell model that mediators of inflammation such as interleukin-1b (IL-1b) did reduce cell growth via induction of senescence-associated secretory phenotype expression [45]. It is well known from pilocytic astrocytoma surgery that residual tumors often switch into senescence after resection despite significant growth prior to surgery.…”