Oncogenic BRAF disrupts thyroid morphogenesis and function via Twist expression
- Weill Cornell Medical College, United States
- University of Ferrara, Italy
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.
Data availability
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Oncogenic BRAF disrupts thyroid morphogenesis and function via Twist expressionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE97096).
Article and author information
Author details
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.
Reviewing Editor
- Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
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.
Version history
- Received: August 16, 2016
- Accepted: March 15, 2017
- Accepted Manuscript published: March 28, 2017 (version 1)
- 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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Oncogenic BRAF disrupts thyroid morphogenesis and function via Twist expression
eLife 6:e20728.
https://doi.org/10.7554/eLife.20728
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