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Oncogenic BRAF disrupts thyroid morphogenesis and function via Twist expression

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Cite this article as: eLife 2017;6:e20728 doi: 10.7554/eLife.20728

Abstract

Thyroid cancer is common, yet the sequence of alterations that promote tumor formation are incompletely understood. Here we describe a novel model of thyroid carcinoma in zebrafish that reveals temporal changes due to BRAFV600E. Through the use of real-time in vivo imaging we observe disruption in thyroid follicle structure that occurs early in thyroid development. Combinatorial treatment using BRAF and MEK inhibitors reversed the developmental effects induced by BRAFV600E. Adult zebrafish expressing BRAFV600E in thyrocytes developed invasive carcinoma. We identified a gene expression signature from zebrafish thyroid cancer that is predictive of disease free survival in patients with papillary thyroid cancer. Gene expression studies nominated TWIST2 as a key effector downstream of BRAF. Using CRISPR/Cas9 to genetically inactivate a TWIST2 orthologue, we suppressed the effects of BRAFV600E and restored thyroid morphology and hormone synthesis. These data suggest that expression of TWIST2 plays a role in an early step of BRAFV600E-mediated transformation.

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The following previously published data sets were used

Article and author information

Author details

  1. Viviana Anelli

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacques A Villefranc

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sagar Chhangawala

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Raul Martinez-McFaline

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Eleonora Riva

    Section of Endocrinology, Department of Medical Science, University of Ferrara, Ferrara, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Anvy Nguyen

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Akanksha Verma

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Rohan Bareja

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhengming Chen

    Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Theresa Scognamiglio

    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Olivier Elemento

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Yariv Houvras

    Department of Surgery, Weill Cornell Medical College, New York, United States
    For correspondence
    yah9014@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0751-3215

Funding

National Institutes of Health (R21CA20254001)

  • Yariv Houvras

National Institutes of Health (T32GM007739)

  • Raul Martinez-McFaline

National Institutes of Health (P50-CA172012)

  • Jacques A Villefranc

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2011-0026) of Weill Cornell Medical College.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: August 16, 2016
  2. Accepted: March 15, 2017
  3. Accepted Manuscript published: March 28, 2017 (version 1)
  4. Version of Record published: April 12, 2017 (version 2)

Copyright

© 2017, Anelli 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.

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