Modeling Braf-induced thyroid cancer development and cell redifferentiation using pluripotent stem cell-derived organoids
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228281 | GEO | 2024/01/02
REPOSITORIES: GEO
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Project description:To investigate the effects of combined BRAF inhibition (dabrafenib) and ERK inhibition (ulixertinib) on papillary and anaplastic thyroid cancer transcriptional reprogramming
2023-06-15 | GSE221329 | GEO
Project description:We performed gene expression profiling in the human papillary thyroid carcinoma (PTC) derived cell line BCPAP harboring BRAFV600E mutation following the treatment with BRAF selective inhibitors.
2021-07-13 | GSE171483 | GEO
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors. RNA-seq was performed on 20 thyroid carcinoma tumors
2015-07-01 | E-GEOD-48953 | biostudies-arrayexpress
Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Total RNA from five murine papillary thyroid carcinoma (PTC) tumors and five murine anaplastic thyroid carcinoma (ATC) tumors was analyzed.
2014-04-02 | E-GEOD-55933 | biostudies-arrayexpress
Project description:Experiment a) Establishment of expression profiles in conventional papillary thyroid carcinomas (PTCs) with a BRAF mutation vs. PTCs without a BRAF mutation and using normal thyroid (TN) specimens as reference. Experiment b) Establishment of expression profiles in follicular adenomas (FAs) of the thyroid and follicular variant of papillary thyroid carcinomas (FVPTCs).
2015-02-16 | GSE54958 | GEO
Project description:Thyroid cancer is common, yet the sequence of alterations that promote tumor formation are incompletely understood. Here we describe a novel model of thyroid carcinoma in zebrafish that reveals temporal changes due to BRAFV600E. Through the use of real-time in vivo imaging we observe disruption in thyroid follicle structure that occurs early in thyroid development. Combinatorial treatment using BRAF and MEK inhibitors reversed the developmental effects induced by BRAFV600E. Adult zebrafish expressing BRAFV600E in thyrocytes developed invasive carcinoma. We identified a gene expression signature from zebrafish thyroid cancer that is predictive of disease free survival in patients with papillary thyroid cancer. Gene expression studies nominated TWIST2 as a key effector downstream of BRAF. Using CRISPR/Cas9 to genetically inactivate a TWIST2 orthologue, we suppressed the effects of BRAFV600E and restored thyroid morphology and hormone synthesis. These data suggest that expression of TWIST2 plays a role in an early step of BRAFV600E-mediated transformation.
2017-03-28 | GSE97096 | GEO
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors.
2015-07-01 | GSE48953 | GEO
Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.
2014-04-02 | GSE55933 | GEO
Project description:Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTC) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC-PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of 8 paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (EMT). This was confirmed by IHC, as vimentin expression was increased and E-cadherin lost in PDTC compared to adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor-beta (TGFbeta) in mediating this process. Accordingly, TGFbeta induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFbeta-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required MAPK pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFbeta-induced EMT, through a MAPK-dependent process. Comparing the transcription profiles of 8 pairs of murine poorly differentiated thyroid cancer and papillary thyroid cancer collected from the same animals by laser capture microdissection. Co-hybridizations were done in triplicate with a single dye flip.
2011-03-22 | E-GEOD-27668 | biostudies-arrayexpress
Project description:Papillary thyroid carcinoma (PTC) is one of the most common forms of thyroid cancer with a cure rate of over 90% after surgery. However, aggressive forms may still occur, and personalized therapeutic strategies are increasingly required. We subjected patient materials from a cohort of patients whose tumors did not harbor BRAF or RAS mutations to genomic and proteomic analysis. In a 23-year-old patient with thyroiditis, we identified by RNA-seq analysis a novel rearrangement leading to a BAIAP2L1-BRAF fusion that kinase-dependently transforms immortalized human thyroid cells. BAIAP2L1-BRAF multimerizes via the dimer interface of the BRAF kinase leading to its activation. Moreover, quantitative proteomic analysis of the same patient samples revealed the upregulation of several proteins including the Ub E3 ligase TRIM25, PDE5A, and PKC-delta. Further, in a cohort of PTC patients, we observed higher expression of TRIM25 and PKC-delta in the tumor and metastatic lesions, when compared to the matched normal tissue. Inhibition of TRIM25, PDE5A and PKC-delta with small molecules or RNA interference affected not only viability and proliferation of BAIAP2L1-BRAF transformed cells, but also the viability, growth and invasion of corresponding 3D spheroid cultures. Apart from unveiling a novel oncogenic BRAF fusion in PTCs, our data may open a novel avenue of therapeutic targeting in human PTCs.
2023-02-22 | PXD034229 | JPOST Repository