title: Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors.
abstract: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr-/- tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Valeria G
authors.initials: VG
authors.lastname: Antico Arciuch
authors.forename: Marika A
authors.initials: MA
authors.lastname: Russo
authors.forename: Mariavittoria
authors.initials: M
authors.lastname: Dima
authors.forename: Kristy S
authors.initials: KS
authors.lastname: Kang
authors.forename: Florence
authors.initials: F
authors.lastname: Dasrath
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
mesh_terms: D000782:Aneuploidy; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse