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Overactivation of SHH signaling induces a cascade of dedifferentiation and oncogenesis in a new mouse model for choroid plexus carcinoma.

Overview

Authors: Levke-Sophie Peter1, Lea Altendorf1,2, Karoline Hack1,2, Vanessa Thaden1,2, Carolin Göbel1,2, Beatrix Mahnke1,2, Christian Krebs3,4, Saskia-L Jauch-Speer3,5, Uwe R Kordes2, Denise Obrecht-Sturm2, Christian Thomas6, Ulrich Schüller1,2,7, Melanie Schoof1,2,8
ORCID iDs: Carolin Göbel, Ulrich Schüller
  1. Research Institute Children’s Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Building N63, 20251 Hamburg, Germany
  2. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  3. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  5. Single Cell Core Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  6. Institute of Neuropathology, University Hospital Münster, Münster, Germany
  7. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  8. Mildred Scheel Cancer Career Centre HaTriCS4, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Institutions: Universität Hamburg (Germany); University Medical Center Hamburg-Eppendorf (Germany); Kinderkrebs-Zentrum Hamburg (Germany); University Cancer Center Hamburg (Germany); University Hospital Münster (Germany)
Journal: Acta neuropathologica communications, volume 14, issue 1, article 176
Dates: received 24 February 2026; accepted 3 August 2026; published online 21 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s40478-026-02402-y · PMID 42629571 · PMCID PMC13499314 · OpenAlex W7203930532
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Preprocessing, Connectivity
Keywords: Choroid Plexus carcinoma, Sonic Hedgehog signaling, Dedifferentiation, Spatial transcriptomics, Mouse model
MeSH: Carcinogenesis*, Carcinoma*, Cell Dedifferentiation*, Choroid Plexus Neoplasms*, Hedgehog Proteins*, Signal Transduction*, Animals, Choroid Plexus, Disease Models, Animal, Mice, Mice, Transgenic, Tumor Suppressor Protein p53, Zinc Finger Protein Gli2 (* major topic)
Topic: Hedgehog Signaling Pathway Studies (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Leibniz-Gemeinschaft
Citations: not cited yet (Europe PMC); 77 references in the paper
Research resources: RFP RRID:AB_10781500, Foxj1 RRID:AB_1078902, Arl13b RRID:AB_2060867, NeuN RRID:AB_2298772, SOX2 RRID:AB_2341193, E-Cadherin RRID:AB_2341210, Transthyretin RRID:AB_2804646, Nestin RRID:AB_2909415, Alexa 555 α-mouse RRID:AB_2943224, anti-Ki67 RRID:AB_302459, anti-SOX2 RRID:AB_358009, anti-OLIG2 RRID:AB_570666, Doublecortin/DCX RRID:AB_732011, RRID:SCR_000154, RRID:SCR_002798, RRID:SCR_003070, RRID:SCR_010943, generation of KEGG pathways RRID:SCR_012773, Read quality was confirmed by FastQC RRID:SCR_014583, Visualizations used ggplot2 RRID:SCR_014601, RRID:SCR_016341, using the ComplexHeatmap package RRID:SCR_017270, Results were visualized in a UMAP RRID:SCR_018217, RRID:SCR_025848

Abstract

Choroid Plexus tumors constitute 10–20% of brain tumors in infancy. Among these, Choroid Plexus Carcinomas (CPC) are highly aggressive and result in poor survival. Details on tumor initiation and oncogenic events remain largely unknown, aside from a high prevalence of TP53 mutations and marked chromosomal instability. We generated hGFAP-cre::lsl-MYCN::lsl-Gli2(N)::Tp53fl/fl mice with recombination activity from embryonic day 13.5 onwards in CNS cells, leading to MYCN and Gli2 activation as well as TP53 inactivation. 84% of the mice developed ventricular tumors within 18 days of life, resembling human CPCs in histology and marker expression. We performed histological and molecular characterization of the resulting tumors and treated tumor cells in vitro. We demonstrate that aberrant Sonic Hedgehog (SHH) signaling during embryonic Choroid Plexus (CP) development triggers a dedifferentiation cascade that reverts mature epithelium to a progenitor-like state. Spatial transcriptomic analysis identifies a distinct cellular hierarchy, where differentiated plexus cells shed their secretory identity to adopt malignant progenitor states. This transformation is accompanied by a transition from multiciliated epithelial cells expressing mature, secretory CP markers to highly proliferative, monociliated progenitors expressing SOX2. This malignant reprogramming activates embryonic developmental programs and induces a critical dependency on cell cycle and DNA repair pathways. Consequently, we identify that these tumor cells cultivated in vitro are vulnerable to ATR and CDK inhibition.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40478-026-02402-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data Availability Statement

All transcriptomic data are available under the GEO Accession number GSE289052 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289052).

All transcriptomic data are available under the GEO Accession number [GSE289052 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289052)](https:/www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE289052).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Funding: added Leibniz-Gemeinschaft

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 5 keywords, 13 MeSH terms, 76 references, 24 RRIDs.

Cite

This paper

Peter, L.-S., Altendorf, L., Hack, K., Thaden, V., Göbel, C., Mahnke, B., Krebs, C., Jauch-Speer, S.-L., Kordes, U. R., Obrecht-Sturm, D., Thomas, C., Schüller, U., & Schoof, M. (2026). Overactivation of SHH signaling induces a cascade of dedifferentiation and oncogenesis in a new mouse model for choroid plexus carcinoma. Acta neuropathologica communications, 14(1), 176. https://doi.org/10.1186/s40478-026-02402-y

BibTeX

@article{peter2026overactivation,
author = {Peter, Levke-Sophie and Altendorf, Lea and Hack, Karoline and Thaden, Vanessa and Göbel, Carolin and Mahnke, Beatrix and Krebs, Christian and Jauch-Speer, Saskia-L and Kordes, Uwe R and Obrecht-Sturm, Denise and Thomas, Christian and Schüller, Ulrich and Schoof, Melanie},
title = {{Overactivation of SHH signaling induces a cascade of dedifferentiation and oncogenesis in a new mouse model for choroid plexus carcinoma}},
journal = {Acta neuropathologica communications},
year = {2026},
month = aug,
volume = {14},
number = {1},
pages = {176},
publisher = {BMC},
issn = {2051-5960},
doi = {10.1186/s40478-026-02402-y},
url = {https://doi.org/10.1186/s40478-026-02402-y},
pmid = {42629571},
pmcid = {PMC13499314}
}

RIS

TY - JOUR
AU - Peter, Levke-Sophie
AU - Altendorf, Lea
AU - Hack, Karoline
AU - Thaden, Vanessa
AU - Göbel, Carolin
AU - Mahnke, Beatrix
AU - Krebs, Christian
AU - Jauch-Speer, Saskia-L
AU - Kordes, Uwe R
AU - Obrecht-Sturm, Denise
AU - Thomas, Christian
AU - Schüller, Ulrich
AU - Schoof, Melanie
TI - Overactivation of SHH signaling induces a cascade of dedifferentiation and oncogenesis in a new mouse model for choroid plexus carcinoma
T2 - Acta neuropathologica communications
J2 - Acta Neuropathol Commun
PY - 2026
DA - 2026/08/21
VL - 14
IS - 1
SP - 176
SN - 2051-5960
PB - BMC
DO - 10.1186/s40478-026-02402-y
UR - https://doi.org/10.1186/s40478-026-02402-y
LA - en
ER -

CSL-JSON

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