Skip to main content

Advertisement

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

Article metrics

  • 902 Accesses

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.

Author information

Correspondence to Johannes Fabian.

Additional information

Johannes Fabian, Desirée Opitz contributed equally to this work.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

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