TY - JOUR
T1 - Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression
AU - Anelli, Viviana
AU - Villefranc, Jacques A.
AU - Chhangawala, Sagar
AU - Martinez-Mcfaline, Raul
AU - Riva, Eleonora
AU - Nguyen, Anvy
AU - Verma, Akanksha
AU - Bareja, Rohan
AU - Chen, Zhengming
AU - Scognamiglio, Theresa
AU - Elemento, Olivier
AU - Houvras, Yariv
N1 - Funding Information:
We are grateful to members of the Houvras laboratory for critical discussion and manuscript review. We gratefully acknowledge Sarah K McMenamin and David M Parichy for providing the zebrafish thyroglobulin promoter construct. We thank Todd Evans and Marco Seandel for critical reading of the manuscript. We thank Jose Cardon Costa and aquatics staff for expert zebrafish husbandry. We thank the Weill Cornell Medicine Optical Microscope Core staff for assistance with confocal imaging. We thank the Weill Cornell Medicine Electron Microscopy & Histology Core facility staff for assistance in preparing histology samples. We thank Chantal Pauli and Theresa McDonald for assistance with zebrafish histology. We thank the Flow Cytometry and Confocal Microscopy Facility at the Hospital of Special Surgery staff for their assistance with cell sorting. Next generation sequencing was performed in the Weill Cornell Medicine Epigenomics Core Facility. We thank Yanwen Jiang and Caitlin Bourque for technical help in performing RNA-seq. This work was supported by the Department of Surgery, Weill Cornell Medical College (YH); a SPORE in Thyroid Cancer, National Institute of Health (NIH) (P50-CA172012) (JV); the Medical Scientist Training Program of General Medical Sciences of the NIH (T32GM007739) to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program (RM). Z Chen was partially supported by the Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06).
Publisher Copyright:
© Anelli et al.
PY - 2017/3/28
Y1 - 2017/3/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85017522316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017522316&partnerID=8YFLogxK
U2 - 10.7554/eLife.20728
DO - 10.7554/eLife.20728
M3 - Article
C2 - 28350298
AN - SCOPUS:85017522316
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e20728
ER -