Nikitski, Alyaksandr1; Rominski, Susan1; Wankhede, Mamta2; Panebianco, Federica1; Altschuler, Daniel L.2, Nikiforov, Yuri E.1
1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
2 Department of Pharmacology and Chemical Biology, Pittsburgh, PA, United States
Background/Purpose: The ALK gene encodes a receptor tyrosine kinase with tissue-specific expression. Recently, we identified ALK fusions, most commonly STRN-ALK, in 1% of papillary, 9% of poorly differentiated (PDTC), and 4% of anaplastic (ATC) thyroid cancers in humans (1). PDTC and ATC have high mortality due to their aggressiveness and poor response to therapy. Animal models of these cancers are needed for better understanding of molecular mechanisms of cancer dedifferentiation and for preclinical studies of targeted therapies.
Objectives: To establish a mouse model of thyroid-specific expression of STRN-ALK and to test whether STRN-ALK fusion drives the development of thyroid cancer with dedifferentiation propensity.
Methods: Three lines of transgenic mice with varying levels of STRN-ALK expression under bovine thyroglobulin promoter were generated and aged. To determine the TSH contribution to the ALK-mediated tumor progression, mice were treated with goitrogen. Thyroids were collected at 3, 6 and 12 months of age and detailed histopathological and immunohistochemical analyses were performed.
Results: Among the three mouse lines, line three with the highest ALK expression developed PDTC by the age of 12 months in 2 out of 15 (13.3%) and 5 out of 14 (35.7%) cases without and with sustained goitrogen treatment, respectively. Thyroid tumors displayed mostly solid growth pattern with spindle-shaped cells and significant reduction of thyroglobulin expression similar to human PDTC.
Discussion/Conclusion: We established the first mouse model of PDTC driven by a single oncogene, STRN-ALK. This model will allow studies of molecular mechanisms of dedifferentiation and treatment of this aggressive thyroid cancer.
- Kelly LM, Barila G, Liu P, et al. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(11):4233-4238. doi:10.1073/pnas.1321937111.