Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.

Autor: Blümel L; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany. lena.bluemel@med.uni-duesseldorf.de.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany. lena.bluemel@med.uni-duesseldorf.de.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany. lena.bluemel@med.uni-duesseldorf.de., Qin N; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Berlandi J; Institute of Neuropathology, University Hospital Münster, Münster, Germany., Paisana E; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal., Cascão R; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal., Custódia C; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal., Pauck D; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Picard D; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Langini M; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Molecular Proteomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Stühler K; Molecular Proteomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Institute of Molecular Medicine, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Meyer FD; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Göbbels S; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Malzkorn B; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Liebau MC; Department of Pediatrics, Center for Family Health, Center for Rare Diseases and Center for Molecular Medicine, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.; Department II of Internal Medicine, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany., Barata JT; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal., Jeibmann A; Institute of Neuropathology, University Hospital Münster, Münster, Germany., Kerl K; Department of Pediatric Hematology and Oncology, University Hospital Münster, Münster, Germany., Erkek S; Hopp Childrens Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany., Kool M; Hopp Childrens Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Pfister SM; Hopp Childrens Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Johann PD; Hopp Childrens Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.; Swabian Childrens´ Cancer Center, Pediatrics and Adolescent Medicine, University Medical Center, Augsburg, Germany., Frühwald MC; Swabian Childrens´ Cancer Center, Pediatrics and Adolescent Medicine, University Medical Center, Augsburg, Germany., Borkhardt A; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany., Reifenberger G; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany., Faria CC; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.; Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisbon, Portugal., Fischer U; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany., Hasselblatt M; Institute of Neuropathology, University Hospital Münster, Münster, Germany., Bartl J; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.; Group for Interdisciplinary Neurobiology and Immunology - INI-research, Institute of Zoology, University of Hamburg, Hamburg, Germany., Remke M; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany. marc.remke@med.uni-duesseldorf.de.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany. marc.remke@med.uni-duesseldorf.de.; Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany. marc.remke@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Sep 20; Vol. 13 (9), pp. 806. Date of Electronic Publication: 2022 Sep 20.
DOI: 10.1038/s41419-022-05243-4
Abstrakt: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.
(© 2022. The Author(s).)
Databáze: MEDLINE
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