A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53fl/fl mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease.

Mouse Models of Pediatric Supratentorial High-grade Glioma Reveal How Cell-of-Origin Influences Tumor Development and Phenotype

“…Despite the histopathologic similarities of these tumors to adult HGG, recent large-scale integrated molecular data have showed distinct molecular differences between adult and pediatric HGG. There are a number of models for pediatric HGG available, in particular for brainstem gliomas (42)(43)(44). These all have in common that they originate from nestin-expressing cells using the N/tv-a mouse line (34).…”

Oncohistones: drivers of pediatric cancers

“…One of the caveats of DIPG models described so far is that they are made without prior knowledge regarding the cell of origin for DIPGs, which is yet unknown. Candidates for the cell of origin for DIPGs include precursor cells in the ventral pons (Nestin + /Vimentin + /Olig2 + ) (Monje et al 2011) or the fourth ventricle floor (Nestin + / Pax3 + ) (Misuraca et al 2016). Despite this, the NSC-based DIPG models show features similar to patient tumors and have provided useful mechanistic insights.…”

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications

“…In a recent study that employed RCAS/TVA system to induce platelet-derived growth factor (PDGF)-B overexpression, p53 loss, and histone 3.3 lysine to methionine mutation (H3.3K27M) researchers were able to genetically engineer a model of pediatric DIPG upon exposure to ectopic PDGF-B ligand and p53-deficiency along with H3.3K27M overexpression [95]. This model could serve as a valuable tool to investigate experimentally the cell of origin and stem-cell perpetrator in pediatric HGGs.…”