Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG selfrenewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.Hedgehog pathway | cancer stem cells | brainstem glioma

Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

“…Of these genes, Pax3, Irx5, and Chl1 were also differentially regulated between the Olig2-compartments of BSG and CG suggesting that they represent biological differences within the tumor cells. As Olig2 characterizes the majority of human BSG, particularly the oligodendroglial (PDGFRA) and H3-K27M subgroups [5,8,50,51], as well as marks a candidate cell-of-origin for BSG [52], the expression profile of these cells has important implications for at least a subset of the human disease.…”

A new era for children with diffuse intrinsic pontine glioma: hope for cure?

“…This hypothesis was supported by the fact that these mutations were not found in exome-sequencing data from adult gliomas [16]. Another group suggested that the Hedgehog signaling pathway, which is highly active in DIPG, could be involved in the origin of DIPG [17]. They observed that unregulated activity of the Hedgehog pathway resulted in hypertrophy of the healthy pons of mice [17].…”

“…Another group suggested that the Hedgehog signaling pathway, which is highly active in DIPG, could be involved in the origin of DIPG [17]. They observed that unregulated activity of the Hedgehog pathway resulted in hypertrophy of the healthy pons of mice [17]. All these exciting new biological insights and discoveries of multiple pathways are helping to increase the understanding of DIPG and developing new multi-targeted therapy approaches for this disease.…”

“…This addresses the second key issue; preclinical models for DIPG are still very rare. To date, only two groups have published on DIPG in vitro models [17,22]. With the lack of DIPG cell lines, in vivo models have been developed using adult glioma cell lines, but these lack the DIPG genotype.…”

“…Moreover, only few animal models show the diffuse growth typical for DIPG [21]. From the few existing DIPG cell cultures, only two groups have reported the development of xenografts thus far [17,22].…”