MYCN transcriptionally represses CD9 to trigger an invasion-metastasis cascade in neuroblastoma

  • Johannes Fabian
  • Desirée Opitz
  • Kristina Althoff
  • Marco Lodrini
  • Kathy Astrahantseff
  • Barbara Hero
  • Ruth Volland
  • Anneleen Beckers
  • Katleen de Preter
  • Nitin S Patil
  • Mohammed L Abba
  • Theresa M Thole
  • Jasmin Wünschel
  • Annette Künkele
  • Jamie Hu
  • Leonille Schweizer
  • Gunhild Mechtersheimer
  • Daniel R Carter
  • Belamy B Cheung
  • Odilia Popanda
  • Andreas von Deimling
  • Kai-Oliver Henrich
  • Frank Westermann
  • Manfred Schwab
  • Jan Koster
  • Rogier Versteeg
  • Glenn M Marshall
  • Frank Speleman
  • Margot Zoeller
  • Heike Allgayer
  • Matthias Fischer
  • Frank Berthold
  • Andreas E Kulozik
  • Olaf Witt
  • Angelika Eggert
  • Johannes H Schulte
  • Hedwig E Deubzer
Open Access
Meeting abstract

Keywords

Neuroblastoma Neuroblastoma Cell Boyden Chamber Assay Poor Treatment Response 450K Methylation 

Meeting abstract

The systemic and resistant nature of neuroblastoma metastasized to distant organs makes it largely incurable with current multimodal treatment. Clinical progression stems mainly from an increasing burden of metastatic colonization. Novel therapeutic perspectives may be won by blocking as yet poorly understood pathways triggering the migration-invasion-metastasis cascade in neuroblastoma. The CD9 cell surface glycoprotein was decoded as a major downstream player and direct target of the recently described GRHL1 tumor suppressor in in-depth transcriptome analyses and ChIP-qRT-PCR. CD9 is known to facilitate carcinoma cell motility and metastasis. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome and predicted poor treatment response in patients with the worst outcome. MYCN and HDAC5 co-localized to the CD9 promoter and repressed transcription. CD9 expression was strongly reduced during progressive development of murine tumors in the TH-MYCN transgenic mouse model of neuroblastoma compared to expression in ganglia from wildtype mice, further supporting MYCN involvement in CD9 transcriptional repression in neuroblastoma cells. We detected differential CD9 methylation in 450K methylation array analyses of primary neuroblastomas, and CD9 hypermethylation was associated with reduced CD9 expression, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to chicken embryo bone marrow. Combined treatment of neuroblastoma cells with inhibitors for HDACs and DNA methyltransferase induced CD9 expression. Our results show CD9 is a critical and indirectly druggable mediator of neuroblastoma cell invasion and metastasis.

Copyright information

© Fabian et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Johannes Fabian
    • 1
  • Desirée Opitz
    • 1
  • Kristina Althoff
    • 2
    • 3
  • Marco Lodrini
    • 4
  • Kathy Astrahantseff
    • 4
  • Barbara Hero
    • 5
  • Ruth Volland
    • 5
  • Anneleen Beckers
    • 6
  • Katleen de Preter
    • 6
  • Nitin S Patil
    • 7
    • 8
  • Mohammed L Abba
    • 7
    • 8
  • Theresa M Thole
    • 4
  • Jasmin Wünschel
    • 4
  • Annette Künkele
    • 4
  • Jamie Hu
    • 1
    • 9
  • Leonille Schweizer
    • 10
  • Gunhild Mechtersheimer
    • 11
  • Daniel R Carter
    • 12
  • Belamy B Cheung
    • 12
  • Odilia Popanda
    • 13
  • Andreas von Deimling
    • 10
    • 14
  • Kai-Oliver Henrich
    • 15
  • Frank Westermann
    • 15
  • Manfred Schwab
    • 15
  • Jan Koster
    • 16
  • Rogier Versteeg
    • 16
  • Glenn M Marshall
    • 12
    • 17
  • Frank Speleman
    • 6
  • Margot Zoeller
    • 18
  • Heike Allgayer
    • 7
    • 8
  • Matthias Fischer
    • 5
    • 19
  • Frank Berthold
    • 5
    • 19
  • Andreas E Kulozik
    • 20
  • Olaf Witt
    • 1
    • 20
  • Angelika Eggert
    • 4
  • Johannes H Schulte
    • 2
    • 3
    • 21
    • 22
  • Hedwig E Deubzer
    • 4
  1. 1.Clinical Cooperation Unit Pediatric ncologyGerman Cancer Research Center (DKFZ), INF 280HeidelbergGermany
  2. 2.Department of Pediatric Hematology & OncologyUniversity Children's Hospital EssenEssenGermany
  3. 3.Translational NeurooncologyGerman Consortium for Translational Cancer Research (DKTK), Partner Site Essen/ DuesseldorfEssenGermany
  4. 4.Department of Pediatric Hematology, Oncology & BMTCharité - University Hospital Berlin, CVKBerlinGermany
  5. 5.Department of Pediatric Hematology and OncologyUniversity of CologneCologneGermany
  6. 6.Center for Medical Genetics Ghent (CMGG)Ghent University Hospital Medical Research Building (MRB)GhentBelgium
  7. 7.Molecular Oncology of Solid Tumors Unit, DKFZ, INF280HeidelbergGermany
  8. 8.Department of Experimental Surgery, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  9. 9.Cornell UniversityIthacaUSA
  10. 10.Department of NeuropathologyUniversity of Heidelberg, INF 224HeidelbergGermany
  11. 11.Department of PathologyUniversity of Heidelberg, INF224HeidelbergGermany
  12. 12.Children's Cancer Institute, UNSWRandwickAustralia
  13. 13.Division of Epigenomics and Cancer Risk Factors, DKFZ, INF 280HeidelbergGermany
  14. 14.Clinical Cooperation Unit Neuropathology, DKFZ, INF280HeidelbergGermany
  15. 15.Neuroblastoma Genetics, DKFZ, INF280HeidelbergGermany
  16. 16.Department of Oncogenomics, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  17. 17.Kids Cancer CentreSydney Children's Hospital RandwickRandwickAustralia
  18. 18.Experimental Surgery and Tumor Cell BiologyUniversity of Heidelberg, INF 365HeidelbergGermany
  19. 19.Center for Molecular Medicine CologneUniversity of CologneCologneGermany
  20. 20.Department of Pediatric Hematology and OncologyUniversity of Heidelberg, INF 430HeidelbergGermany
  21. 21.Translational Neuro-Oncology, West German Cancer Center (WTZ)University Hospital Essen, University Duisburg-EssenEssenGermany
  22. 22.Center for Medical BiotechnologyUniversity Duisburg-EssenEssenGermany

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