Pediatric pilocytic astrocytoma (PA) is a common type of low-grade brain tumour in children, influenced by specific genetic changes. Researchers at Washington University School of Medicine in St. Louis have conducted a study using advanced stem cell techniques to investigate the genetic alterations that cause PA and how they affect tumour growth. Their findings shed light on molecular pathways that could lead to new targeted therapies, offering hope for better treatment options for children with PA.

The study is published in the journal Genes & Development.

PA is mainly driven by two genetic changes: the loss of the Neurofibromatosis type 1 (NF1) gene and a rearrangement of KIAA1549: BRAF, which fuses with the KIAA1549 gene. These anomalies activate the MEK/ERK signalling pathway, which promotes cell growth, a key factor in tumour development.

Although it is known that MEK/ERK activation is linked to tumours in PA, the exact way MEK affects cell growth in human brain cells has been unclear. This study uses human induced pluripotent stem cells (hiPSCs) with these PA-related genetic changes to understand the process better.

The researchers discovered that β-catenin, a protein, is crucial for MEK-dependent cell growth. MEK controls β-catenin activity through two separate mechanisms; IRX2 affects the gene that produces β-catenin, while NPTX1 stabilises the β-catenin protein, preventing its breakdown.

When examining hipsc-derived neural cells with the NF1 deletion or KIAA1549: BRAF fusion, the team observed increased cell growth and ERK activation, which decreased when treated with an MEK inhibitor.

The study also analysed actual PA tumours, finding higher β-catenin levels in patient tumour samples and in lab models. Blocking MEK or β-catenin reduced tumour cell growth, showing these tumours rely on this pathway.

IRX2 and NPTX1 both enhance β-catenin signalling, but in different ways. IRX2 controls β-catenin production at the genetic level, while NPTX1 prevents the protein's degradation.

This research not only clarifies the role of MEK/β-catenin signaling in PA but also suggests possible targets for treatment. Understanding how IRX2 and NPTX1 regulate this pathway can help develop new drugs to inhibit β-catenin signalling, offering a potential strategy to slow tumour growth in children with PA.

The complex interplay of genetic changes and signalling pathways in pediatric pilocytic astrocytoma highlights the intricate nature of cancer biology. This study provides important insights and opens new possibilities for developing treatments that could improve outcomes for young patients facing this disease.