Endocrinol Metab.  2019 Mar;34(1):11-22. 10.3803/EnM.2019.34.1.11.

Mouse Models as a Tool for Understanding Progression in Braf(V600E)-Driven Thyroid Cancers

• Landa I
• Knauf JA

• KMID: 2441674
• DOI: http://doi.org/10.3803/EnM.2019.34.1.11

Abstract

The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting BRAF and RAS proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 (TP53) and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase (TERT) promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the BRAF(V600E)-driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of BRAF(V600E)-driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic BRAF(V600E)-driven thyroid cancers.

Keyword

Proto-oncogene proteins B-raf; Thyroid neoplasms; Mice, transgenic

MeSH Terms

Animals
Carcinogenesis
Catalytic Domain
Mice*
Mice, Transgenic
Negotiating
Proto-Oncogene Proteins B-raf
Proto-Oncogenes
Telomerase
Thyroid Gland*
Thyroid Neoplasms*
Proto-Oncogene Proteins B-raf
Telomerase

Figure

• 

  Fig. 1 Genetic alterations in human BRAFV600E-driven thyroid cancers. Oncoprint showing the most frequent mutations identified in BRAFV600E-mutant of papillary thyroid carcinomas from the The Cancer Genome Atlas study (PTC-TCGA, n=235, left), poorly-differentiated thyroid carcinomas (PDTCs, n=32, middle), and anaplastic thyroid cancers (ATCs, n=85, right). Mutation data compiled from TCGA [1], Kunstman et al. [2], Landa et al. [4], Ibrahimpasic et al. [3], Pozdeyev et al. [5], and Memorial Sloan Kettering Cancer Center Clinical Runs, as of November 1st, 2018. TP53, tumor protein p53; TERT, telomerase reverse transcriptase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SWI/SNF, mating-type switching/sucrose non-fermenting complex; NF2, neurofibromin 2; CDKN2A, cyclin dependent kinase inhibitor 2A; RBM10, RNA binding motif protein 10.

• 

  Fig. 2 M2-like macrophage infiltration in oncogenic BRAF-driven mouse anaplastic thyroid cancers (ATCs). Immune deconvolution using CIBERSORT [46] was performed on transcriptomic data from the following mouse models: McFadden et al. [21] (GSE55933) TPO-CreERT2/Braf (papillary thyroid carcinoma [PTC]) and TPO-CreERT2/BrafCA/Trp53f/f (ATC). Knauf et al. [8] (GSE118022) PTC, LSL-Braf/TPO-Cre: ATC, TPO-Cre/LSL-rtTAiresGFP/tetO-myc-BRAFV600E/Trp53f/f. Bars show the relative level of M2-like macrophages in the indicated model and cancer histologies. TPO-CreERT2, thyroid peroxidase driven cre/estrogen receptor ligand binding domain fusion; BrafCA, Cre-activated BrafV600E allele; Trp53, transformation related protein 53; LSL, lox-stop-lox; rtTAiresGFP, reverse tetracycline transcription activator-internal ribosomal entry site-green fluorescent protein; tetO-mycBRAFV600E, tetracycline resistant operator-MYC proto oncogene tagged BRAFV600E.

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