DNA methylation and transposable elements: a new field in childhood cancer research

Alterations in DNA methylation is a hallmark of most cancers including glioma. We hypothesize that a key event following loss of DNA methylation in glioma is the activation of transposable elements (TEs). This activation could result in a viral mimicry, where the tumor cells falsely sense that they are infected by a virus, leading to an interferon response, making tumor cells vulnerable. Also, these cells are likely to present TE-derived neoantigens that can be targeted using immunotherapies.

To explore this idea we will use glioma resurrections and primary tumor spheres. We will perform a detailed characterization of the DNA-methylation landscape in glioma resurrections. This will result in a single cell map of DNA methylation and transcription in human glioma with a focus TEs. We will also investigate if global loss of DNA methylation results in activation of TEs and a downstream interferon response. For these experiments both genetic and pharmacological means will be used to inhibit methylation to boost TE-expression. These experiments will identify the molecular mechanisms that silence TEs in glioma, resulting in a pharmacological strategy to activate them.