LMO1 Cooperates with MYCN to Promote Neuroblastomagenesis and Metastasis

A genome-wide association study (GWAS) identified the LIM-domain-only transcriptional cofactor LMO1 as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. However, the function of LMO1 in neuroblastoma has not been well characterized. Zhu, Zhang, and colleagues investigated the role of LMO1 in a zebrafish model of MYCN-driven neuroblastoma using an LMO1 transgene. Expression of LMO1 was not sufficient to induce neuroblastoma in zebrafish, but LMO1 cooperated with MYCN overexpression to accelerate tumorigenesis, resulting in an earlier neuroblastoma onset and increased penetrance. Transgenic expression of LMO1 increased the proliferation of hyperplastic sympathoadrenal cells in the inter-renal gland (IRG), thereby enhancing neuroblastoma tumorigenesis. Further, coexpression of LMO1 and MYCN increased the rate of distant metastases in the zebrafish model of neuroblastoma, consistent with human tumors in which LMO1 overexpression has been associated with metastatic disease at diagnosis. In human neuroblastoma cells with MYCN amplification, overexpression of LMO1 enhanced cell invasion and migration. RNA sequencing of a human neuroblastoma cell line showed that LMO1 overexpression resulted in enrichment of gene signatures related to tumor cell–extracellular matrix (ECM) interactions, and these findings were confirmed in neuroblastoma cell lines with high and low expression of endogenous LMO1. Specifically, LMO1 expression was associated with upregulation of LOXL3, ITGA2B, ITGA3, and ITGA5 in human and zebrafish neuroblastoma cells, and these changes in gene expression were associated with increased collagen deposition and matrix remodeling to increase ECM stiffness and support metastasis. Collectively, these findings demonstrate that LMO1 synergizes with MYCN to promote neuroblastoma initiation, progression, and metastasis in vivo, providing a mechanism by which the GWAS-identified LMO1 risk allele may increase neuroblastoma susceptibility.

Zhu S, Zhang X, Weichert-Leahey N, Dong Z, Zhang C, Lopez G, et al. LMO1 synergizes with MYCN to promote neuroblastoma initiation and metastasis. Cancer Cell 2017;32:310–23.e5.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.