Dynamic characterization of tumor-microenvironment factors that drive pediatric low-grade gliomas

Pediatric low-grade gliomas (pLGGs) are the most common brain cancers diagnosed in children, often leading to life-long neurological impairments. Whilst targeted inhibitors exist, their effects are often short-lived, highlighting the urgent need for innovative treatments. Notably, some pLGG tumors spontaneously regress with age, suggesting that changes in the tumor microenvironment can arrest tumor growth. In this work, we aim to characterize which signaling interactions promote the growth of pLGG cells and how these interactions change dynamically with time. To achieve this, we have optimized a protocol for introducing pLGG mutations into developing mouse brains via in utero electroporation. This study revealed that brains harboring the common KIAA1549::BRAF fusion mutation have a striking phenotype characterized by increased astrocyte reactivity and myeloid cell infiltration. To better understand how signals derived from immune cells may impact pLGG cell fitness, we are additionally performing a high-throughput cytokine screen. We are developing barcoded cytokine constructs tethered to the cell membrane to comprehensively screen the impact of cytokine signaling on the growth of neural stem cells engineered to overexpress common pLGG mutations. Together this work aims to unravel which signaling factors govern the age-dependent growth of pLGG tumors, which may reveal targetable aspects of the tumor microenvironment amenable to therapeutic intervention.