EPEN-01. Understanding the role of the Hippo signalling pathway in ependymoma tumour biology

The Hippo signalling pathway is a tumour suppressive kinase cascade which results in phosphorylation and cytoplasmic sequestration of transcriptional coactivators YAP/TAZ. An upstream regulator of this pathway is Merlin, encoded for by the NF2 gene. Mutations in NF2 are characteristic of a tumour predisposition syndrome called NF2-related schwannomatosis, which causes the development of schwannomas, meningiomas and ependymomas. Ependymomas are tumours of ependymal cells, which occur throughout the central nervous system. There are numerous subtypes which come with varying prognoses. The type caused by NF2-related schwannomatosis is classical spinal ependymoma. Additionally, a type of supratentorial ependymoma is caused by fusion mutations in YAP and MAMLD1/C11orf95 which result in its constitutive translocation. This project aims to explore the effect of Merlin loss and subsequent dysregulation of Hippo signalling on the immune microenvironment of ependymomas. Using immunohistochemistry to compare immune cell infiltration in 10 myxopapillary and 10 classical spinal ependymomas, we have shown that there is a significant correlation between macrophage infiltration and YAP/TAZ nuclear localisation in all ependymomas examined using Pearson’s correlation (p-value = 0.033, R-value 0.48). We have also identified a significant correlation between the genetic expression signatures for M2 macrophage infiltration and CYR61 expression in publicly available ependymoma RNA-sequencing datasets using Pearson’s correlation (p-value = 0.039, R-value 0.48), with CYR61 being a target gene of Hippo signalling. Future work aims to explore a broader range of immune cells in primary samples by multiplex immunohistochemistry, to explore further genetic correlations by methylation testing, and to include a YAP1-fusion ependymoma cohort for analysis. This work is funded by University of Plymouth Peninsula Medical School, and primary samples were provided by BRAINUK.