Dataset Information

Establishment and characterization of cell lines from a novel mouse model of poorly differentiated thyroid carcinoma: powerful tools for basic and preclinical research.

ABSTRACT:

Background

Poorly differentiated and anaplastic thyroid carcinomas have a rather poor prognosis. The development of relevant model systems to unravel in vitro and in vivo the molecular mechanisms governing the resistance of these tumors to therapy, as well as to test novel drug combinations, is a clear priority for thyroid-focused research.

Methods

Several novel cell lines were established from tumors developed by mice engineered to simultaneously express a loss-of-function Pten allele and an oncogenic Kras allele.

Results

Similar to most poorly differentiated thyroid tumors, these cell lines are characterized by simultaneous activation of the PI3K and MAPK pathways, by the presence of wild-type, functional p53, and by the severe downregulation of thyroid differentiation markers, including sodium-iodide symporter (NIS). Further, they display a highly glycolytic phenotype. They can be grafted to syngeneic, immunocompetent hosts, and easily metastasize to the lungs.

Conclusions

These mouse cell lines are a novel and invaluable tool that can be used to develop innovative therapeutic approaches to poorly differentiated carcinomas in a more physiological context than using xenografts of human cell lines in immunocompromised mice.

SUBMITTER: Dima M

PROVIDER: S-EPMC3162646 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Publications

Establishment and characterization of cell lines from a novel mouse model of poorly differentiated thyroid carcinoma: powerful tools for basic and preclinical research.

Dima Mariavittoria M Miller Kelly A KA Antico-Arciuch Valeria Gabriela VG Di Cristofano Antonio A

Thyroid : official journal of the American Thyroid Association 20110718 9

<h4>Background</h4>Poorly differentiated and anaplastic thyroid carcinomas have a rather poor prognosis. The development of relevant model systems to unravel in vitro and in vivo the molecular mechanisms governing the resistance of these tumors to therapy, as well as to test novel drug combinations, is a clear priority for thyroid-focused research.<h4>Methods</h4>Several novel cell lines were established from tumors developed by mice engineered to simultaneously express a loss-of-function Pten a ...[more]

PMID: 21767142

Similar Datasets

Project description:BACKGROUND:Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS:We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS:Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. CONCLUSIONS:These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. FUNDING:This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

Dataset Information

Establishment and characterization of cell lines from a novel mouse model of poorly differentiated thyroid carcinoma: powerful tools for basic and preclinical research.

Background

Methods

Results

Conclusions

Publications

Establishment and characterization of cell lines from a novel mouse model of poorly differentiated thyroid carcinoma: powerful tools for basic and preclinical research.

Similar Datasets

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