Mouse Model of Poorly Differentiated Thyroid Carcinoma Driven by STRN-ALK Fusion

摘要

Chromosomal rearrangements of theALKgene, which lead to constitutive activation of ALK tyrosine kinase, are found in various cancers. In thyroid cancers,ALKfusions, most commonly theSTRN-ALKfusion, are detected in papillary thyroid cancer and with higher frequency in poorly differentiated and anaplastic thyroid cancers. Our aim was to establish a mouse model of thyroid-specific expression ofSTRN-ALKand to test whether this fusion drives the development of thyroid cancer with a propensity for dedifferentiation. TransgenicTg-STRN-ALKmice with thyroglobulin-controlled expression ofSTRN-ALKwere generated and aged with or without goitrogen treatment. Thyroids from these mice were subjected to histologic and immunohistochemical analysis. Transgenic mice with thyroid-specific expression ofSTRN-ALKdeveloped poorly differentiated thyroid tumors by the age of 12 months in 22% of mice without goitrogen treatment and in 36% of mice with goitrogen treatment. Histologically and immunohistochemically, the tumors resembled poorly differentiated thyroid cancers in humans, demonstrating a solid growth pattern with sheets of round or spindle-shaped cells, decreased expression of thyroglobulin, and a tendency to lose E-cadherin. In this study, we report a novel mouse model of poorly differentiated thyroid cancer driven by theSTRN-ALKoncogene with phenotypic features closely recapitulating human tumor, and with a more pronounced phenotype after additional thyroid-stimulating hormone stimulation.