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  • Meeting abstract
  • Open Access

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

  • Johannes Fabian1,
  • Desirée Opitz1,
  • Kristina Althoff2, 3,
  • Marco Lodrini4,
  • Kathy Astrahantseff4,
  • Barbara Hero5,
  • Ruth Volland5,
  • Anneleen Beckers6,
  • Katleen de Preter6,
  • Nitin S Patil7, 8,
  • Mohammed L Abba7, 8,
  • Theresa M Thole4,
  • Jasmin Wünschel4,
  • Annette Künkele4,
  • Jamie Hu1, 9,
  • Leonille Schweizer10,
  • Gunhild Mechtersheimer11,
  • Daniel R Carter12,
  • Belamy B Cheung12,
  • Odilia Popanda13,
  • Andreas von Deimling10, 14,
  • Kai-Oliver Henrich15,
  • Frank Westermann15,
  • Manfred Schwab15,
  • Jan Koster16,
  • Rogier Versteeg16,
  • Glenn M Marshall12, 17,
  • Frank Speleman6,
  • Margot Zoeller18,
  • Heike Allgayer7, 8,
  • Matthias Fischer5, 19,
  • Frank Berthold5, 19,
  • Andreas E Kulozik20,
  • Olaf Witt1, 20,
  • Angelika Eggert4,
  • Johannes H Schulte2, 3, 21, 22 and
  • Hedwig E Deubzer4
Contributed equally
Molecular and Cellular Pediatrics20152(Suppl 1):A13

Published: 1 July 2015


NeuroblastomaNeuroblastoma CellBoyden Chamber AssayPoor Treatment Response450K 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.


Authors’ Affiliations

Clinical Cooperation Unit Pediatric ncology, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany
Department of Pediatric Hematology & Oncology, University Children's Hospital Essen, Essen, Germany
Translational Neurooncology, German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/ Duesseldorf, Essen, Germany
Department of Pediatric Hematology, Oncology & BMT, Charité - University Hospital Berlin, CVK, Berlin, Germany
Department of Pediatric Hematology and Oncology, University of Cologne, Cologne, Germany
Center for Medical Genetics Ghent (CMGG), Ghent University Hospital Medical Research Building (MRB), Ghent, Belgium
Molecular Oncology of Solid Tumors Unit, DKFZ, INF280, Heidelberg, Germany
Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Cornell University, Ithaca, USA
Department of Neuropathology, University of Heidelberg, INF 224, Heidelberg, Germany
Department of Pathology, University of Heidelberg, INF224, Heidelberg, Germany
Children's Cancer Institute, UNSW, Randwick, Australia
Division of Epigenomics and Cancer Risk Factors, DKFZ, INF 280, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, DKFZ, INF280, Heidelberg, Germany
Neuroblastoma Genetics, DKFZ, INF280, Heidelberg, Germany
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Kids Cancer Centre, Sydney Children's Hospital Randwick, Randwick, Australia
Experimental Surgery and Tumor Cell Biology, University of Heidelberg, INF 365, Heidelberg, Germany
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Department of Pediatric Hematology and Oncology, University of Heidelberg, INF 430, Heidelberg, Germany
Translational Neuro-Oncology, West German Cancer Center (WTZ), University Hospital Essen, University Duisburg-Essen, Essen, Germany
Center for Medical Biotechnology, University Duisburg-Essen, Essen, Germany


© 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 (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.