PNR-23: SHH AND WNT SIGNALLING ARE UPREGULATED IN HUMAN INTRAOCULAR MEDULLOEPITHELIOMA AND LEAD TO RETINAL TUMOR-LIKE LESIONS IN THE MOUSE

Intraocular medulloepithelioma (IOMEPL) is a rare eye tumor, mostly diagnosed in the first decade of life. Although the total number of cases is very low it is the second most common primary intraocular tumor in childhood after retinoblastoma. Many tumors show contact to the ciliary body, but some localize within the retina. They show striking morphological similarities to embryonal tumors with multilayered rosettes (ETMRs), which occur in the central nervous system. Moreover, both entities overexpress LIN28A, but differ with respect to methylation patterns and the spectrum of mutations. While ETMRs show an upregulation of the WNT, SHH and NOTCH pathways, nothing is known about pathway alterations in IOMEPL. In order to identify novel treatment strategies for IOMEPL, we asked if known cancer-related pathways are functionally activated in IOMEPL. Using the Pancancer Pathways Panel, we performed NanoString nCounter analyses of 8 IOMEPLs. Interestingly, IOMEPLs showed a gene expression pattern similar to ETMRs with activated WNT, SHH and NOTCH signaling pathways. In order to elucidate the impact of Wnt and Shh signaling in embryonal eye development and for tumor formation, we created an inducible mouse model that showed constitutively active Wnt- and Shh- signaling in Sox2-positive cells of the immature eye. Depending on the time point of induction, these mice developed tumor-like lesions in the retina. Our results suggest a critical role of Wnt and Shh signalling in the formation of IOMEPL and indicate that early Sox2 positive cells within the retina may be a potential cell of origin for these tumors.