Novel Anaplastic Thyroid Cancer PDXs and Cell Lines: Expanding Preclinical Models of Genetic Diversity.
Aged
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Middle Aged
Phenotype
Prognosis
Survival Rate
Thyroid Carcinoma, Anaplastic
/ genetics
Thyroid Neoplasms
/ genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
BRAF mutation
TP53 mutation
anaplastic thyroid carcinoma
patient-derived xenograft
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
21 10 2021
21 10 2021
Historique:
received:
27
08
2020
pubmed:
20
6
2021
medline:
15
12
2021
entrez:
19
6
2021
Statut:
ppublish
Résumé
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. We developed distinct ATC PDX models concurrently with cell lines and characterized them in vitro and in vivo. 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. 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%. 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.
Identifiants
pubmed: 34147031
pii: 6306517
doi: 10.1210/clinem/dgab453
pmc: PMC8530744
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e4652-e4665Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA016672
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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