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Progression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling

Oncogene volume 30, pages 3153–3162 (2011)Cite this article

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Abstract

Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTCs) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC–PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of eight paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial–mesenchymal transition (EMT). This was confirmed by immunohistochemistry, as vimentin expression was increased and E-cadherin lost in PDTC compared with adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor (TGF)β in mediating this process. Accordingly, TGFβ-induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFβ-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required mitogen-activated protein kinase (MAPK) pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFβ-induced EMT, through a MAPK-dependent process.

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Acknowledgements

This study was supported by NIH CA 50706, and a grant from the Margot Rosenberg Pulitzer Foundation. We are grateful to the MSKCC Genetically Engineered Mouse Phenotyping core facility and Dr Katia Manova of the MSKCC Molecular Cytology core for help with immunohistochemical experiments.

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Author notes

  1. M A Sartor

    Present address: 6Current address: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.,

  2. Y E Nikiforov

    Present address: 7Current address: Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,

Authors and Affiliations

  1. Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J A Knauf, E Lundsmith, M Ryder, M Salzano & J A Fagin

  2. Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA

    M A Sartor & M Medvedovic

  3. Department of Pathology, University of Cincinnati, Cincinnati, OH, USA

    Y E Nikiforov

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    T J Giordano

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    R A Ghossein

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Knauf, J., Sartor, M., Medvedovic, M. et al. Progression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling. Oncogene 30, 3153–3162 (2011). https://doi.org/10.1038/onc.2011.44

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