1. Cancer Biology
Download icon

Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

  1. Shuning He
  2. Marc R Mansour
  3. Mark W Zimmerman
  4. Dong Hyuk Ki
  5. Hillary M Layden
  6. Koshi Akahane
  7. Evisa Gjini
  8. Eric D de Groh
  9. Antonio R Perez-Atayde
  10. Shizhen Zhu
  11. Jonathan A Epstein
  12. A Thomas Look  Is a corresponding author
  1. Harvard Medical School, United States
  2. Perelman School of Medicine at the University of Pennsylvania, United States
Research Article
  • Cited 18
  • Views 2,075
  • Annotations
Cite this article as: eLife 2016;5:e14713 doi: 10.7554/eLife.14713

Abstract

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical 'developmental tumor', NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.

Article and author information

Author details

  1. Shuning He

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Marc R Mansour

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mark W Zimmerman

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dong Hyuk Ki

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hillary M Layden

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Koshi Akahane

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Evisa Gjini

    Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Eric D de Groh

    Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Antonio R Perez-Atayde

    Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shizhen Zhu

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jonathan A Epstein

    Department of Cell and Developmental Biology, Penn Cardiovascular Institute, and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. A Thomas Look

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    For correspondence
    thomas_look@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All zebrafish studies and maintenance of the animals were performed in accordance with Dana-Farber Cancer Institute IACUC-approved protocol (#02-107).

Reviewing Editor

  1. Richard J Gilbertson, Cambridge Cancer Center, CRUK Cambridge Institute, United Kingdom

Publication history

  1. Received: January 26, 2016
  2. Accepted: April 26, 2016
  3. Accepted Manuscript published: April 27, 2016 (version 1)
  4. Version of Record published: June 9, 2016 (version 2)

Copyright

© 2016, He et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,075
    Page views
  • 528
    Downloads
  • 18
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Medicine
    Maria Ochoa de Olza
    Insight

    Organ-on-chip approaches could help researchers to better predict the toxicity of cancer immunotherapy drugs.

    1. Cancer Biology
    2. Cell Biology
    Brian Spurlock et al.
    Short Report

    Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks'; level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.