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Comprehensive Genetic Characterization of Human Thyroid Cancer Cell Lines: A Validated Panel for Preclinical Studies.

ABSTRACT: PURPOSE:Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. EXPERIMENTAL DESIGN:We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. RESULTS:Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. CONCLUSIONS:This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

SUBMITTER: Landa I

PROVIDER: S-EPMC6522280 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Comprehensive Genetic Characterization of Human Thyroid Cancer Cell Lines: A Validated Panel for Preclinical Studies.

Landa Iñigo I Pozdeyev Nikita N Korch Christopher C Marlow Laura A LA Smallridge Robert C RC Copland John A JA Henderson Ying C YC Lai Stephen Y SY Clayman Gary L GL Onoda Naoyoshi N Tan Aik Choon AC Garcia-Rendueles Maria E R MER Knauf Jeffrey A JA Haugen Bryan R BR Fagin James A JA Schweppe Rebecca E RE

Clinical cancer research : an official journal of the American Association for Cancer Research 20190208 10

<h4>Purpose</h4>Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers.<h4>Experimental design</h4>We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers.<h4>Results</h4>Unsuper ...[more]

PMID: 30737244

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Project description:IntroductionInvestigation of normal human thyroid function using in vitro culture systems is dependent on cells that recapitulate physiology of differentiated thyrocytes. Primary thyrocytes retain features of the native organ but have limited lifespan in culture. Immortalized thyrocytes offer an alternative if challenges maintaining phenotypic stability can be overcome to retain functional features of primary cells.Materials and methodsCI-SCREEN immortalization technology was applied to normal human thyroid tissue to generate four cell line variants. The lines were characterized for transgene integration, biomarker expression, genomic stability, and proliferation rates. Thyroid Stimulating Hormone (TSH)-dependent morphology, thyroglobulin production, thyroxine hormone synthesis, and viability were assessed using conventional 2D monolayer and 3D microtissue culture formats in huThyrEC or h7H medium.ResultsDespite differential transgene profiles, the lines had similar biomarker expression patterns and proliferation rates. In 2D culture there was no thyroxine synthesis or changes in viability, but TSH-dependent thyroglobulin production was more significant for several lines in h7H than huThyrEC medium. Comparatively, in 3D microtissues, TSH-dependent thyroglobulin induction was greater for cell lines in h7H medium. Synthesis of thyroxine in one cell line was higher than background with TSH exposure, but not significantly different than control.DiscussionImmortalization of primary human thyrocytes yielded transgenic lines of epithelial origin. When evaluated in 2D or 3D culture formats, h7H medium supported thyroglobulin production to a greater magnitude than huThyrEC medium. One cell line cultured in 3D microtissue format marginally recapitulated T4 synthesis under continuous TSH exposure.ConclusionSelect human thyroid cell lines exhibited morphological and functional features of primary thyrocytes and are a novel resource for in vitro disease modeling and toxicity testing that will enable reproducible culture models more representative of normal human thyroid function.

Dataset Information

Comprehensive Genetic Characterization of Human Thyroid Cancer Cell Lines: A Validated Panel for Preclinical Studies.

Publications

Comprehensive Genetic Characterization of Human Thyroid Cancer Cell Lines: A Validated Panel for Preclinical Studies.

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