Mouse Model of Thyroid Cancer Progression and Dedifferentiation Driven by STRN-ALK Expression and Loss of p53: Evidence for the Existence of Two Types of Poorly Differentiated Carcinoma.
Thyroid tumor progression from well-differentiated cancer to poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) involves step-wise dedifferentiation associated with loss of iodine avidity and poor outcomes. ALK fusions, typically STRN-ALK, are found with higher incidence in human PDTC compared with well-differentiated cancer and, as previously shown, can drive the development of murine PDTC. The aim of this study was to evaluate thyroid cancer initiation and progression in mice with concomitant expression of STRN-ALK and inactivation of the tumor suppressor p53 (Trp53) in thyroid follicular cells.  Transgenic mice with thyroid-specific expression of STRN-ALK and biallelic p53 loss were generated and aged on a regular diet or with methimazole and sodium perchlorate goitrogen treatment. Development and progression of thyroid tumors were monitored by using ultrasound imaging, followed by detailed histological and immunohistochemical evaluation. Gene expression analysis was performed on selected tumor samples by using RNA-Seq and quantitative RT-PCR.  In mice treated with goitrogen, the first thyroid cancers appeared at 6 months of age, reaching 86% penetrance by the age of 12 months, while a similar rate (71%) of tumor occurrence in mice on regular diet was observed by 18 months of age. Histological examination revealed well-differentiated papillary thyroid carcinomas (PTC) (n = 26), PDTC (n = 21), and ATC (n = 8) that frequently coexisted in the same thyroid gland. The tumors were frequently lethal and associated with the development of lung metastasis in 24% of cases. Histological and immunohistochemical characteristics of these cancers recapitulated tumors seen in humans. Detailed analysis of PDTC revealed two tumor types with distinct cell morphology and immunohistochemical characteristics, designated as PDTC type 1 (PDTC1) and type 2 (PDTC2). Gene expression analysis showed that PDTC1 tumors retained higher expression of thyroid differentiation genes including Tg and Slc5a5 (Nis) as compared with PDTC2 tumors.  In this study, we generated a new mouse model of multistep thyroid cancer dedifferentiation with evidence of progression from PTC to PDTC and ATC. Further, PDTC in these mice showed two distinct histologic appearances correlated with levels of expression of thyroid differentiation and iodine metabolism genes, suggesting a possibility of existence of two PDTC types with different functional characteristics and potential implication for therapeutic approaches to these tumors.
['Nikitski|Alyaksandr V|AV|', 'Rominski|Susan L|SL|', 'Condello|Vincenzo|V|', 'Kaya|Cihan|C|', 'Wankhede|Mamta|M|', 'Panebianco|Federica|F|', 'Yang|Hong|H|', 'Altschuler|Daniel L|DL|', 'Nikiforov|Yuri E|YE|']
D000077548:Anaplastic Lymphoma Kinase D000818:Animals D013956:Antithyroid Agents D002148:Calmodulin-Binding Proteins D054337:Cell Dedifferentiation D002454:Cell Differentiation D004195:Disease Models, Animal D018450:Disease Progression D008565:Membrane Proteins D008713:Methimazole D051379:Mice D018345:Mice, Knockout D008822:Mice, Transgenic D009419:Nerve Tissue Proteins D015514:Oncogene Proteins, Fusion D010472:Perchlorates D000081246:RNA-Seq D017670:Sodium Compounds D027981:Symporters D013954:Thyroglobulin D000077273:Thyroid Cancer, Papillary D065646:Thyroid Carcinoma, Anaplastic D013964:Thyroid Neoplasms D059467:Transcriptome D016159:Tumor Suppressor Protein p53
thyroid cancer dedifferentiation STRN-ALK p53 poorly differentiated carcinoma