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Published on: November 17, 2021
The molecular and cell biology of pediatric low-grade gliomas
1Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
Insights
Pilocytic astrocytoma (PA) in children arises from specific genetic changes. Research using Nf1 mouse models suggests these pediatric brain tumors develop from particular cell types in distinct brain regions.
Area of Science:
- Pediatric neuro-oncology
- Cancer genetics
- Tumor microenvironment
Background:
- Pilocytic astrocytoma (PA) is the most common pediatric glial tumor.
- PA is associated with KIAA1549:BRAF fusions (sporadic) or neurofibromatosis 1 (NF1).
- Tumor location (NF1-PA in optic pathway/brainstem, sporadic PA in cerebellum) suggests additional factors beyond known mutations.
Purpose of the Study:
- Investigate the cellular and regional origins of pediatric gliomas.
- Explore the role of the tumor microenvironment and genomic modifiers in gliomagenesis.
- Utilize genetically engineered mouse (GEM) models to study PA development.
Main Methods:
- Review of advances in Nf1-GEM modeling.
- Analysis of experimental evidence on cell of origin, signaling pathways, and microenvironment.
- Comparison of NF1- and KIAA1549:BRAF-driven gliomagenesis.
Main Results:
- Nf1-GEM models provide insights into pediatric glioma development.
- Evidence supports specific cell types and brain locations for Nf1- and KIAA1549:BRAF-induced gliomas.
- Gliomagenesis likely involves more than just NF1 inactivation or BRAF fusion.
Conclusions:
- Pediatric gliomas, including pilocytic astrocytoma, arise from specific cell types in defined brain regions.
- Understanding these origins is crucial for developing effective therapeutic strategies.
- Nf1-GEM models are valuable tools for studying pediatric brain tumor biology.
Abstract:
Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15-20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the NF1 tumor suppressor gene or expression of the KIAA1549:BRAF transcript. Several etiologic explanations include differential susceptibilities of preneoplastic neuroglial cell types in different brain regions to these glioma-causing genetic changes, contributions from non-neoplastic cells and signals in the tumor microenvironment, and genomic modifiers that confer glioma risk. As clinically-faithful rodent models of sporadic PA are currently under development, Nf1 genetically-engineered mouse (GEM) models have served as tractable systems to study the role of the cell of origin, deregulated intracellular signaling, non-neoplastic cells in the tumor microenvironment and genomic modifiers in gliomagenesis. In this report, we highlight advances in Nf1-GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations.
