Year: 2018
Type: article
Abstract: Diffuse intrinsic pontine glioma (DIPG) is pediatric brain tumor that occurs in the pons and for which there is no treatment. Mutations in Activin-A Receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor, are highly recurrent and specific for DIPG. We used the Sleeping Beauty Transposase (SB) system to deliver plasmids encoding NRASV12 and a short hair pin for TP53 (shp53) with or without ACVR1-G328V, the most frequent of the six ACVR1 mutations found in DIPG, into the brainstem of neonatal mice, to generate endogenous tumors with DIPG mutations. Tumor development was monitored by measuring luciferase activity in vivo. Moribund stage animals were perfused and processed for histology. H&E staining demonstrated that the tumors developed in the brainstem and cerebellum. Tumors induced with NRAS/shp53/ACVR1 G328V had an increased median survival, MS = 129 dpi, compared to control group NRAS/shp53, MS = 65 dpi (p=0.0002). In vitro and in vivo, tumors or tumor neruospheres (NS) harboring ACVR1-G328V exhibit elevated phospho-Smad1/5, transducer of the BMP pathway. RNA-seq analysis confirms that the TGF-Beta pathway is upregulated in tumor NS harboring ACVR1 G328V. From this data we also identified that signaling pathways involved in regulating pluripotency of stem cells and focal adhesion are differentially regulated. In summary, we used the SB transposase system to develop a mouse model that accurately represents the molecular biology of DIPGs with ACVR1 G328V mutations. Tumors arise in the brainstem and ACVR1 G328V prolongs survival through upregulation of the BMP-Smad1/5 pathways. In the future, we aim to elucidate the mechanisms by which ACVR1 contributes to tumor development to develop novel therapies for ACVR1 mutant DIPGs.
Source: Neuro-Oncology
Institution: University of Michigan
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2900367254