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Activation of Wnt/ß-catenin signaling is critical for the tumorigenesis of choroid plexus.
Hoa Ho, Kim; Trapp, Marleen; Guida, Catello; Ivanova, Ekaterina L; De Jaime-Soguero, Anchel; Jabali, Ammar; Thomas, Christian; Salasova, Alena; Bernatík, Ondrej; Salio, Chiara; Horschitz, Sandra; Hasselblatt, Martin; Sassoe-Pognetto, Marco; Cajánek, Lukás; Ishikawa, Hiroshi; Schroten, Horst; Schwerk, Christian; Acebrón, Sergio P; Angel, Peter; Koch, Philipp; Patrizi, Annarita.
Afiliación
  • Hoa Ho K; Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Trapp M; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • Guida C; Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Ivanova EL; Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • De Jaime-Soguero A; Hector Institute for Translational Brain Research gGmbH, Mannheim, Germany.
  • Jabali A; German Cancer Research Center, Heidelberg, Germany.
  • Thomas C; Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, Heidelberg, Germany.
  • Salasova A; Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.
  • Bernatík O; Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • Salio C; Hector Institute for Translational Brain Research gGmbH, Mannheim, Germany.
  • Horschitz S; German Cancer Research Center, Heidelberg, Germany.
  • Hasselblatt M; Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • Sassoe-Pognetto M; Danish Research Institute of Translational Neuroscience DANDRITE, and Center of Excellence PROMEMO, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • Cajánek L; Laboratory of Cilia and Centrosome Biology, Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czechia.
  • Ishikawa H; Section of Animal Physiology and Immunology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia.
  • Schroten H; Department of Veterinary Sciences, Turin University, Grugliasco, Italy.
  • Schwerk C; Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • Acebrón SP; Hector Institute for Translational Brain Research gGmbH, Mannheim, Germany.
  • Angel P; German Cancer Research Center, Heidelberg, Germany.
  • Koch P; Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • Patrizi A; Department of Neurosciences "Rita Levi Montalcini", Turin University, Turin, Italy.
Neuro Oncol ; 2024 Aug 31.
Article en En | MEDLINE | ID: mdl-39215664
ABSTRACT

BACKGROUND:

Choroid plexus (ChP) is the secretory epithelial structure located in brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of the tumor pathology and limited availability of valid models.

METHODS:

Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/ß-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and over-expression of Wnt/ß-catenin pathway genes. 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC.

RESULTS:

We discovered that Wnt/ß-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/ß-catenin signaling for survival. Constitutive Wnt/ß-catenin pathway activation, either through knock-out of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of Wnt/ß-catenin pathway in ChP organoids, through treatment with a potent GSK3ß inhibitor, reduced the differentiation of mature ChP epithelia cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids.

CONCLUSIONS:

Our research identifies Wnt/ß-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido