Research

How our senses (vision, hearing, taste, smell, touch) respond to environmental stimuli is crucial in our daily lives. Recent findings suggest that gliomas (a type of brain tumor) take advantage of the sensory system to support neoplastic transformation.^1,2 Using genetically engineered mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma, where tumors develop in a specific location at a specific time, we have demonstrated that light (visual experience)-induced neuronal activity is required for glioma initiation (Figure 1).¹ Light is “sensed” by photoreceptors (rods, cones, and intrinsically photosensitive retinal ganglion cells [ipRGCs]), which are specialized neurons that transform the physical information about light into neuronal signals.

Thus, one research focus in the Pan lab is deciphering how sensations and their corresponding neuronal activity modulate tumorigenesis (Figure 2). For example, we are currently testing whether and how each photoreceptor light-sensing pathway contributes to optic gliomagenesis.

We are quickly gaining knowledge about how neurons interact with tumor (neoplastic) cells to support their proliferation, migration, etc. However, we have very limited knowledge about the role of neuronal activity during neoplastic transformation, especially about how neurons interact with the preneoplastic cells (Figure 3).

Using genetically engineered mice of the neurofibromatosis type 1 (NF1) tumor predisposition syndrome that represent preneoplastic stages of glioma (Figure 4)³ and various neuromodulatory approaches, we seek to understand how neuron-glia interactions are transformed during gliomagenesis.

As shown in Figure 4,³ immunohistochemistry of oligodendrocyte precursor cells (OPCs) (PDGFRα+; putative cell-of-origin for several glioma types) mice that were genetically wild type (WT)-equivalent (Nf1^WT: Nf1^+/+, Nf1^fl/+, or Nf1^fl/fl), OPC-specific heterozygous Nf1-mutant (Nf1^OPC-iHet: Nf1^fl/+;Pdgfra::CreER; i: inducible; tamoxifen injected at P24), and OPC-specific Nf1-null (Nf1^OPC-iKO: Nf1^fl/fl;Pdgfra::CreER, tamoxifen injected at P24). Nf1 monoallelic and biallelic inactivation was induced at 3 weeks of age, and brains were analyzed 16 weeks later. PDGFRα immunohistochemistry (green) revealed globally increased OPC density in the brains of Nf1^OPC-iKO mice and focal OPC hyperdensities (dash lines) in Nf1^OPC-iHet mice. 

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome and a neurogenetic disease that causes neurological issues in learning, motor function, executive function, etc. Patients with NF1 tumors receive chemotherapy that may further exacerbate their existing neurological issues. The influence of Nf1 mutations and/or therapy on neurological function is unclear.

Our preliminary data suggest that Nf1 mutations and NF1 therapy can both influence oligodendroglial function (Figure 5).³

Our current studies will determine the underlying mechanism and identify potential therapeutic targets for both inhibiting gliomagenesis and alleviating neurological impairment.