LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis

Shizhen Zhu, Xiaoling Zhang, Nina Weichert-Leahey, Zhiwei Dong, Cheng Zhang, Gonzalo Lopez, Ting Tao, Shuning He, Andrew C. Wood, Derek Oldridge, Choong Yong Ung, Janine H. van Ree, Amish Khan, Brittany M. Salazar, Edroaldo Lummertz da Rocha, Mark W. Zimmerman, Feng Guo, Hong Cao, Xiaonan Hou, Saravut (John) WerohaAntonio R. Perez-Atayde, Donna S. Neuberg, Alexander Meves, Mark A Mc Niven, Jan Van Deursen, Hu Li, John M. Maris, A. Thomas Look

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination. High expression of LMO1 is associated with neuroblastoma (NB) metastases. Zhu et al. show that LMO1 synergizes with MYCN to promote NB development and metastasis in zebrafish and that LMO1 elevates expression of genes affecting tumor cell-extracellular matrix interaction and promotes NB cell invasion.

Original languageEnglish (US)
Pages (from-to)310-323.e5
JournalCancer Cell
Volume32
Issue number3
DOIs
StatePublished - Sep 11 2017

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Keywords

  • ECM
  • LMO1
  • metastasis
  • MYCN
  • neuroblastoma
  • tumorigenesis
  • zebrafish model

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Zhu, S., Zhang, X., Weichert-Leahey, N., Dong, Z., Zhang, C., Lopez, G., Tao, T., He, S., Wood, A. C., Oldridge, D., Ung, C. Y., van Ree, J. H., Khan, A., Salazar, B. M., Lummertz da Rocha, E., Zimmerman, M. W., Guo, F., Cao, H., Hou, X., ... Look, A. T. (2017). LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell, 32(3), 310-323.e5. https://doi.org/10.1016/j.ccell.2017.08.002