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SRP102546
Danio rerio
14 Downloadable Samples
IlluminaHiSeq2000
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. Overall design: 3 embryo tg-TOM (tg:TdTomato), 3 embryo tg-BRAFV600E-TOM, 3 adult tg-TOM and 5 adult tg-BRAFV600E-TOM biological replicates were sequenced. Strains with tg:TdTomato express the TdTomato fluorophore under control of the zebrafish thyroglobulin promoter (tg).
Publication Title
Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression.
Sample Metadata Fields
No sample metadata fields
View Samples- Danio rerio
- 8 Downloadable Samples
- IlluminaHiSeq2500
Description
We report the gene expression comparison of zebrafish melanocytes and melanomas. These comparisons were used for integrative genomic studies that identified the BMP factor GDF6 as a new oncogene that is specifically expressed in melanomas. Overall design: Examination of gene expression in two different cell types
Publication Title
Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Danio rerio
- 8 Downloadable Samples
- NextSeq 500
Description
Selenium, one of a class of selenocysteine-containing proteins (selenoproteins), is an essential micronutrient known for its cancer prevention properties. Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LCMS/ MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels. Overall design: 4 WT zebrafish samples and 4 SepH mutant samples
Publication Title
Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis.
Sample Metadata Fields
Subject
View Samples- Danio rerio, Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Danio rerio
- 7 Downloadable Samples
- Illumina HiSeq 2000
Description
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer. Overall design: WT (4 replicates) and homozygous rabl3-TR41 mutant (3 replicates) larval zebrafish at 21 days of age.
Publication Title
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 197 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples. Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent complex patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs.
Publication Title
High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes.
Sample Metadata Fields
Age
View Samples- Mus musculus
- 63 Downloadable Samples
- Illumina HiSeq 2500
Description
A subset of GC B cells that have stopped cycling, upregulated CD38 and downregulated BCL-6 is functionally verified as GC-derived memory B cell precursors (GC-MPs). RNA-seq analyses of the transcriptome were used to probe the developmental trajectory of these cells and their responses to IL-9, a cytokine that is found to drive the memory development from the GC. Overall design: Differential gene expression analyses between GC-MP cells and regular GC B cells in G1 phase (GC-MPP cells); Gene expression profiling of different GC subsets in comparison to memory B cells and plasma cells; acute effects of in vivo IL-9 or anti-IL-9 treatment on GC-MP or GC-MPP cells.
Publication Title
Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children the disease resolves but in some it becomes chronic. To investigate whether the two forms of the disease are similar or separate entities we performed DNA microarray analysis of T-cells from newly diagnosed children and children with chronic ITP. We found complete separation of the expression files between the two forms of the disease. Furthermore, the gene expression of several cytokines differed between the two forms of the disease. This was also reflected in plasma with increased levels of IL-16 and TWEAK and lower levels of IL-4 in newly diagnosed compared with chronic ITP. Thus, our data indicate that the two forms of the disease may be separate entities.
Publication Title
Differences in gene expression and cytokine levels between newly diagnosed and chronic pediatric ITP.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Mus musculus, Homo sapiens
- 9 Downloadable Samples
Illumina MouseRef-8 v2.0 expression beadchip, Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Differential gene expression is assessed in substantia nigra and basal ganglia of neurodegenertion with brain iron accumulation cases (BIA) compared to matched normal controls (c).
Publication Title
Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples