title: Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression.
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 BRAFV600Ein 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 BRAFV600Eand restored thyroid morphology and hormone synthesis. These data suggest that expression of TWIST2 plays a role in an early step of BRAFV600E-mediated transformation.
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Viviana
authors.initials: V
authors.lastname: Anelli
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Villefranc
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chhangawala
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Raul
authors.initials: R
authors.lastname: Martinez-McFaline
authors.affiliation: Section of Endocrinology, Department of Medical Science, University of Ferrara, Ferrara, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Riva
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Anvy
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York City, United States.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York City, United States.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York City, United States.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York City, United States.
authors.forename: Rohan
authors.initials: R
authors.lastname: Bareja
authors.affiliation: Department of Healthcare Policy & Research, Weill Cornell Medical College, New York City, United States.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: Scognamiglio
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York City, United States.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York City, United States.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.|Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.|Department of Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York City, United States.
authors.forename: Yariv
authors.identifier: 0000-0003-0751-3215
authors.initials: Y
authors.lastname: Houvras
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D009024:Morphogenesis; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000196:embryology* / Q000502:physiology*; D013963:Thyroid Hormones / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000473:pathology*; D000071417:Twist-Related Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D015027:Zebrafish
chemical_list: D050505:Mutant Proteins; D013963:Thyroid Hormones; D000071417:Twist-Related Protein 2; D048493:Proto-Oncogene Proteins B-raf
keywords: EMT; cancer biology; epithelial cells; gene expression; human biology; medicine; protooncogenes; zebrafish