Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma

Abstract Intraocular medulloepithelioma (IO-MEPL) is a rare embryonal ocular neoplasm, prevalently occurring in children. IO-MEPLs share histomorphological features with CNS embryonal tumors with multilayered rosettes (ETMRs), referred to as intracranial medulloepitheliomas. While Sonic hedgehog (SH...

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Main Authors:	Matthias Dottermusch, Piotr Sumisławski, Julia Krevet, Maximilian Middelkamp, Hannah Voß, Bente Siebels, Harald Bartsch, Karl Sotlar, Peter Meyer, Stephan Frank, Andrey Korshunov, Markus Glatzel, Ulrich Schüller, Julia E. Neumann
Format:	article
Language:	EN
Published:	Nature Publishing Group 2021
Subjects:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Online Access:	https://doaj.org/article/5056055f68924b4582e954273d6ffd22
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spelling	oai:doaj.org-article:5056055f68924b4582e954273d6ffd222021-11-21T12:15:26ZCo-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma10.1038/s41389-021-00369-02157-9024https://doaj.org/article/5056055f68924b4582e954273d6ffd222021-11-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00369-0https://doaj.org/toc/2157-9024Abstract Intraocular medulloepithelioma (IO-MEPL) is a rare embryonal ocular neoplasm, prevalently occurring in children. IO-MEPLs share histomorphological features with CNS embryonal tumors with multilayered rosettes (ETMRs), referred to as intracranial medulloepitheliomas. While Sonic hedgehog (SHH) and WNT signaling pathways are crucial for ETMR pathogenesis, the impact of these pathways on human IO-MEPL development is unclear. Gene expression analyses of human embryonal tumor samples revealed similar gene expression patterns and significant overrepresentation of SHH and WNT target genes in both IO-MEPL and ETMR. In order to unravel the function of Shh and Wnt signaling for IO-MEPL pathogenesis in vivo, both pathways were activated in retinal precursor cells in a time point specific manner. Shh and Wnt co-activation in early Sox2- or Rax-expressing precursor cells resulted in infiltrative ocular lesions that displayed extraretinal expansion. Histomorphological, immunohistochemical, and molecular features showed a strong concordance with human IO-MEPL. We demonstrate a relevant role of WNT and SHH signaling in IO-MEPL and report the first mouse model to generate tumor-like lesions with features of IO-MEPL. The presented data may be fundamental for comprehending IO-MEPL initiation and developing targeted therapeutic approaches.Matthias DottermuschPiotr SumisławskiJulia KrevetMaximilian MiddelkampHannah VoßBente SiebelsHarald BartschKarl SotlarPeter MeyerStephan FrankAndrey KorshunovMarkus GlatzelUlrich SchüllerJulia E. NeumannNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 11, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Matthias Dottermusch Piotr Sumisławski Julia Krevet Maximilian Middelkamp Hannah Voß Bente Siebels Harald Bartsch Karl Sotlar Peter Meyer Stephan Frank Andrey Korshunov Markus Glatzel Ulrich Schüller Julia E. Neumann Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
description	Abstract Intraocular medulloepithelioma (IO-MEPL) is a rare embryonal ocular neoplasm, prevalently occurring in children. IO-MEPLs share histomorphological features with CNS embryonal tumors with multilayered rosettes (ETMRs), referred to as intracranial medulloepitheliomas. While Sonic hedgehog (SHH) and WNT signaling pathways are crucial for ETMR pathogenesis, the impact of these pathways on human IO-MEPL development is unclear. Gene expression analyses of human embryonal tumor samples revealed similar gene expression patterns and significant overrepresentation of SHH and WNT target genes in both IO-MEPL and ETMR. In order to unravel the function of Shh and Wnt signaling for IO-MEPL pathogenesis in vivo, both pathways were activated in retinal precursor cells in a time point specific manner. Shh and Wnt co-activation in early Sox2- or Rax-expressing precursor cells resulted in infiltrative ocular lesions that displayed extraretinal expansion. Histomorphological, immunohistochemical, and molecular features showed a strong concordance with human IO-MEPL. We demonstrate a relevant role of WNT and SHH signaling in IO-MEPL and report the first mouse model to generate tumor-like lesions with features of IO-MEPL. The presented data may be fundamental for comprehending IO-MEPL initiation and developing targeted therapeutic approaches.
format	article
author	Matthias Dottermusch Piotr Sumisławski Julia Krevet Maximilian Middelkamp Hannah Voß Bente Siebels Harald Bartsch Karl Sotlar Peter Meyer Stephan Frank Andrey Korshunov Markus Glatzel Ulrich Schüller Julia E. Neumann
author_facet	Matthias Dottermusch Piotr Sumisławski Julia Krevet Maximilian Middelkamp Hannah Voß Bente Siebels Harald Bartsch Karl Sotlar Peter Meyer Stephan Frank Andrey Korshunov Markus Glatzel Ulrich Schüller Julia E. Neumann
author_sort	Matthias Dottermusch
title	Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
title_short	Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
title_full	Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
title_fullStr	Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
title_full_unstemmed	Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
title_sort	co-activation of sonic hedgehog and wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/5056055f68924b4582e954273d6ffd22
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Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma

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