# Interplay between low levels of GAS7 expression and MYCN overexpression and its impact on neuroblastoma metastasis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $363,713

## Abstract

Neuroblastoma (NB), the most common extracranial solid tumor in children, typically presents at diagnosis with
evidence of widespread metastasis, especially in patients with amplification of the MYCN oncogene. This
subgroup has a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy.
Attempts to improve the treatment of disseminated NB have been impeded by the lack of a detailed
understanding of the multistep cellular and molecular pathogenesis of this complex form of the tumor. Thus,
new mechanistic insights leading to safer and more effective treatments for metastatic NB are urgently needed.
This proposal grew from whole-genome sequencing analyses of primary NB samples from 135 patients, in
which we identified a novel deletion of a growth arrest-specific gene 7 (GAS7, located on chromosome
17p13.1), in a subset of patients with high-risk NB defined by MYCN amplification. Further analysis showed
that low levels of GAS7 expression are associated with advanced-stage, MYCN amplification and a poor
clinical outcome, while knockout of gas7 in a zebrafish model of NB with MYCN overexpression promotes
hematogenous metastasis of tumor cells to sites commonly seen in patients with this disease. We also found
that MYCN can bind indirectly to the GAS7 promoter region, leading to its transcriptional repression, while
reduced expression of GAS7 can increase MYCN protein levels. Hence, the central hypothesis of this
application is that, in addition to cases with the heterozygous deletion of 17p, over- or amplified expression of
MYCN can downregulate GAS7 expression and maintain at deficient levels of this adaptor protein. This, in turn,
appears to maintain MYCN protein expression at high levels, facilitating dissociation of tumor cells from the
primary tumor and their subsequent dissemination. This hypothesis will be tested in three specific aims: 1) To
probe the interplay between MYCN overexpression and low levels of GAS7 expression in metastatic NB, 2) To
dissect the MYCN-induced cascade of downstream transcriptional and signaling changes in the context of
GAS7 deficiency that lead to metastasis in high-risk NB, and 3) To assess the contribution of GAS7 deficiency
to the timing of NB dissemination and the ability of GAS7 overexpression to block or attenuate MYCN-driven
tumor metastasis, and to evaluate in vivo the effect of MYCN overexpression-GAS7 deficiency on NB
metastasis using different murine models. The major innovation of this proposal is the use of emerging
technology with a forward-looking integration of host and tumor genomics in a high-throughput animal model to
dissect the interplay between low levels of GAS7 expression and MYCN overexpression in NB metastasis. The
significance of this study is threefold: it will (i) shed new light on the contributions of MYCN to early NB
metastasis via its effects on adhesion, motility, and invasion, (ii) clarify the mechanism(s) that underlie
MYCN’s cooperation with ...

## Key facts

- **NIH application ID:** 10048193
- **Project number:** 1R01CA240323-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Shizhen Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,713
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048193

## Citation

> US National Institutes of Health, RePORTER application 10048193, Interplay between low levels of GAS7 expression and MYCN overexpression and its impact on neuroblastoma metastasis (1R01CA240323-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048193. Licensed CC0.

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