Cancer as a Neural Circuit Disease

# Diffuse midline glioma: when development and cancer intersect *Evidence guide: Established classification and developmental-state observations. State resemblance does not establish a universal cell of origin.* The brain contains neurons and glia, once dismissed as mere glue. Astrocytes support neurons and help regulate synapses and blood flow. Oligodendrocytes wrap axons in myelin, speeding signals. And microglia, the resident immune cells, come from a separate lineage. Oligodendrocytes come from oligodendrocyte precursor cells, or OPCs. OPCs are spread throughout the brain, persist into adulthood, and are a major dividing population. They can divide, or differentiate into myelinating oligodendrocytes. And, unusually for glia, OPCs receive synapses from neurons. Neuronal activity also shapes glial development. In 2014, the Monje Lab used light to stimulate neurons in the premotor cortex of awake mice. The activity made OPCs divide, increased new oligodendrocytes and myelin in that circuit, and was associated with improved motor function: myelin can adapt to how a circuit is used. Now to cancer. Gliomas are tumors whose cells resemble glia. High-grade gliomas are the aggressive, malignant forms. Glioblastoma is one type, most common in adults. But childhood high-grade gliomas are biologically distinct, and are not simply small versions of adult glioblastoma. One pediatric-type tumor is diffuse midline glioma, or DMG. It arises in midline structures: the pons, the thalamus, and the spinal cord. In the pons it has long been called DIPG, diffuse intrinsic pontine glioma. It mostly affects children, median age around seven at DIPG diagnosis, though young adults can develop it too. Most DMGs share a defining molecular change: the World Health Organization names the tumor ‘diffuse midline glioma, H3 K27-altered’. Usually this is a single point mutation, H3K27M, in a histone gene. In a large international registry, up to ninety percent of DIPGs carried such a mutation. What is a histone? DNA in the nucleus is wrapped around histone proteins, forming chromatin. Histone tails carry chemical tags that help decide which genes are open for reading and which stay silent. One key silencing tag is three methyl groups on lysine 27 of histone H3: H3K27me3. In H3K27M, lysine 27 is replaced by methionine. The mutant histone inhibits PRC2, the complex that writes this silencing mark, so the mark is lost across much of the genome, even though only a fraction of histones are mutant. It is not simple erasure: the mark is depleted globally but retained, or even increased, at some sites. Because chromatin helps lock in cell identity, this change is thought to help keep cells in an immature, precursor-like state. Single-cell sequencing found H3K27M gliomas are dominated by malignant cells resembling OPCs, and these OPC-like cells are the most proliferative. Why is DMG so hard to treat? The pons controls breathing, swallowing, and movement, so surgery is usually impossible. Tumor cells infiltrate diffusely among healthy brain cells, and molecular heterogeneity and the protective brain environment resist therapy. Radiation is standard and gives temporary benefit. In the largest DIPG registry study, median survival was about eleven months. Sources: [ginhoux2010](https://doi.org/10.1126/science.1194637), [bergles2016](https://doi.org/10.1101/cshperspect.a020453), [bergles2000](https://doi.org/10.1038/35012083), [gibson2014](https://doi.org/10.1126/science.1252304), [louis2021](https://doi.org/10.1093/neuonc/noab106), [hoffman2018](https://doi.org/10.1200/JCO.2017.75.9308), [lewis2013](https://doi.org/10.1126/science.1232245), [bender2013](https://doi.org/10.1016/j.ccr.2013.10.006), [chan2013](https://doi.org/10.1101/gad.217778.113), [filbin2018](https://doi.org/10.1126/science.aao4750).