Yuan Pan

Brain tumors have now surpassed leukemia to become the most common malignancies in childhood. Gliomas, a subset of primary central nervous system (CNS) tumors characterized by glial morphology, are the most prevalent of these tumors and can be either high- or low-grade. Prognosis and therapeutic approaches significantly differ between high-grade and low-grade gliomas, with generally poor survival rates for pediatric high-grade gliomas (pHGG) and more favorable outcomes for low-grade gliomas (pLGG). Historically, treatment has consisted of maximally safe surgical resection with or without radiation or chemotherapy, with the therapeutic plan dictated by age, tumor histology, grading and the extent of resection. However, extensive investigation into the molecular drivers of tumorigenesis over the last two decades has improved our understanding of glioma biology, resulting in changes to the classification criteria for these tumors as well as the development of new therapeutic agents targeting critical oncogenic pathways. This has begun to shift clinical practice for some tumor types, such as BRAF-altered LGG. In this review, we summarize our current classification of pediatric gliomas as well as their pathogenesis and treatment, with a particular focus on how biological insights have led to changes in current clinical practice, as well as how ongoing studies in tumor biology may evolve into the next generation of novel treatment strategies.

Neuronal activity instructs a broad range of biological processes, including the regulation of cancers of both the central and peripheral nervous systems. Studies across multiple cancer types have established that neuronal activity regulates tumor progression through diverse mechanisms, including direct synaptic communication, neurotransmitter and neuropeptide signaling, activity-dependent paracrine signaling, and bioelectrical signaling. In turn, tumors actively remodel neural circuits through altered neuronal excitability, axonogenesis, neuronal reprogramming, and nerve injury, establishing bidirectional interactions that reinforce malignant progression. Importantly, neural regulation of cancer is highly context-dependent, with the same neural circuits exerting tumor-promoting or tumor-restraining effects depending on the cancer type, disease stage, neuronal subtype, and surrounding microenvironment. Neuron-tumor interactions engage diverse cellular components of the tumor microenvironment, including immune, stromal, vascular, and glial cells, extending neural regulation beyond direct effects on cancer cells. Communication between peripheral tumors and the central nervous system further reveals organism-wide neural regulation of cancer. Together, these findings establish neuronal activity as a fundamental regulator of tumor biology and highlight neuron-cancer signaling and neuromodulation as promising therapeutic targets across diverse malignancies.

Background: Vision impairment is a significant concern for children with neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). While carboplatin-containing chemotherapy is often first-line therapy for NF1-OPG, it does not consistently improve visual function. Furthermore, chemotherapy is associated with altered white matter microstructure in individuals with NF1-OPG, suggesting a detrimental effect on oligodendroglia. We analyzed the tumor-independent effects of carboplatin on oligodendrocytes in Nf1-mutant mice and evaluated pharmacological strategies for reducing this chemotherapy-associated toxicity. Methods: Carboplatin- or vehicle-treated Nf1+/− mice or Nf1-mutant optic glioma cells were employed to assess the effects of restorative interventions on optic nerve oligodendrocytes in vivo and tumor cell growth in vitro, respectively. Results: Clinically relevant carboplatin dosing induced oligodendrocyte loss and impaired myelin sheath structure in the optic nerves of Nf1+/− mice, an effect not observed following vinca alkaloids or MEK inhibitor (selumetinib) treatment. Carboplatin downregulates genes essential for cholesterol biosynthesis and decreases cholesterol levels in Nf1+/− optic nerves, such that dietary cholesterol supplementation after carboplatin exposure restored oligodendrocyte numbers. Carboplatin also increases the density of monocytes (microglia/macrophages) in the Nf1+/− optic nerves. Using PLX5622 (a CSF1R inhibitor) to reduce monocyte numbers or using clemastine to promote the generation and survival of oligodendrocytes, alleviated the oligodendrocyte loss caused by carboplatin treatment. Notably, PLX5622 and clemastine reduced the viability of Nf1-mutant optic glioma tumor cells. Conclusions: Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure.

Interactions between sensory neurons and tumor cells are increasingly recognized as critical contributors to tumor progression and cancer-associated pain. Here, we describe a reproducible protocol for the isolation and culture of adult mouse dorsal root ganglion (DRG) neurons, followed by functional and molecular assays to assess their responses to tumor-derived secreted factors. Adult DRG were dissected, enzymatically digested with Liberase DH, and dissociated into single neurons. The cells were plated on laminin-coated coverslips and maintained in defined culture conditions that promote neuronal survival while minimizing glial overgrowth. Subsequently, the cultured neurons were exposed to tumor cells' conditioned medium to model paracrine signaling at the neuron-tumor interface. Functional responses were monitored by live cell calcium imaging using fluorescent indicators, enabling quantification of neuronal activity and stimulus-specific responsiveness. In parallel, neuronal stress and injury are evaluated by ATF3 immunostaining. Together, these complementary approaches provide a powerful platform to investigate how tumor-secreted factors sensitize or activate sensory neurons. This protocol integrates adult DRG culture, tumor-conditioned medium treatment, calcium imaging, and molecular readouts into a single workflow, enabling researchers to dissect mechanisms of neuron-tumor communication. The method is broadly applicable to studies of cancer neuroscience, pain signaling, and the identification of secreted mediators that modulate neuronal function in disease contexts.

Neurofibromatosis type 1 (NF1) is among the most common neurogenetic disorders and is associated with an increased risk of developing tumors in the nervous system. Additionally, up to 80% of patients with NF1 experience neurological complications, including deficits in attention, memory, and executive function. Significant effort has been dedicated to studying how NF1 mutations autonomously dysregulate neuronal function. Increasing evidence indicates that NF1 mutations also dysregulate the oligodendroglial lineage that contributes to neurological issues in NF1. Here, we summarize our current understanding of how NF1 mutations impact the oligodendroglial lineage homeostasis and plasticity. We also discuss gaps in knowledge, potential therapeutic strategies, and future directions.

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4–24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

The cognitive side effects of cancer treatment are common, but no targeted therapy exists yet to treat or prevent such neurological sequelae. We explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.