|Title||Novel Anaplastic Thyroid Cancer PDXs and Cell Lines: Expanding Preclinical Models of Genetic Diversity.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Maniakas, A, Henderson, YC, Hei, H, Peng, S, Chen, Y, Jiang, Y, Ji, S, Cardenas, M, Chiu, Y, Bell, D, Williams, MD, Hofmann, M-C, Scherer, SE, Wheeler, DA, Busaidy, NL, Dadu, R, Wang, JR, Cabanillas, ME, Zafereo, M, Johnson, FM, Lai, SY|
|Journal||J Clin Endocrinol Metab|
|Date Published||2021 Oct 21|
|Keywords||Aged, Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Middle Aged, Phenotype, Prognosis, Survival Rate, Thyroid Carcinoma, Anaplastic, Thyroid Neoplasms, Tumor Cells, Cultured, Xenograft Model Antitumor Assays|
CONTEXT: Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust preclinical thyroid cancer models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models may resemble patient tumors by recapitulating key genetic alterations and gene expression patterns, making them excellent preclinical models for drug response evaluation.
OBJECTIVE: We developed distinct ATC PDX models concurrently with cell lines and characterized them in vitro and in vivo.
METHODS: Fresh thyroid tumor from patients with a preoperative diagnosis of ATC was surgically collected and divided for concurrent cell line and PDX model development. Cell lines were created by generating single cells through enzymatic digestion. PDX models were developed following direct subcutaneous implantation of fresh tumor on the flank of immune compromised/athymic mice.
RESULTS: Six ATC PDX models and 4 cell lines were developed with distinct genetic profiles. Mutational characterization showed one BRAF/TP53/CDKN2A, one BRAF/CDKN2A, one BRAF/TP53, one TP53 only, one TERT-promoter/HRAS, and one TERT-promoter/KRAS/TP53/NF2/NFE2L2 mutated phenotype. Hematoxylin-eosin staining comparing the PDX models to the original patient surgical specimens show remarkable resemblance, while immunohistochemistry stains for important biomarkers were in full concordance (cytokeratin, TTF-1, PAX8, BRAF). Short tandem repeats DNA fingerprinting analysis of all PDX models and cell lines showed strong concordance with the original tumor. PDX successful establishment rate was 32%.
CONCLUSION: We have developed and characterized 6 novel ATC PDX models with 4 matching cell lines. Each PDX model harbors a distinct genetic profile, making them excellent tools for preclinical therapeutic trials.
|Alternate Journal||J Clin Endocrinol Metab|
|PubMed Central ID||PMC8530744|
|Grant List||P30 CA016672 / CA / NCI NIH HHS / United States |
P30CA016672 / CA / NCI NIH HHS / United States