Expression profiling of budding cells in colorectal cancer suggests an EMT-like phenotype and molecular subtype switching
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB11806 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1141830.fastq.gz | Fastqsanger.gz | |||
| ERR1141840.fastq.gz | Fastqsanger.gz | |||
| ERR1141831.fastq.gz | Fastqsanger.gz | |||
| ERR1141841.fastq.gz | Fastqsanger.gz | |||
| ERR1141832.fastq.gz | Fastqsanger.gz |
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Project description:Tumour buds undergo phenotype switching while detaching from the main tumour, as they acquire more migratory characteristics and tend to stop proliferating. Simultaneously, an EMT-like signature is observed in the tumour buds under the form of active WNT, TGF and receptor tyrosine kinase signalling. In addition, FOXA2 and RUNX2 well known transcription factors in other cancer types were also differentially expressed in the buds compared to the main tumour mass, hinting at the potential role in tumour budding and initiation of metastasis in colorectal cancer.
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Project description:Tumour budding, described as the presence of single cells or small clusters of up to five tumour cells at the invasive margin, is established as a prognostic marker in colorectal carcinoma. In the present study, we aimed to investigate the molecular signature of tumour budding cells and the corresponding tumour bulk.Tumour bulk and budding areas were microdissected and processed for RNA-sequencing. As little RNA was obtained from budding cells, a special low-input mRNA library preparation protocol was used. Gene expression profiles of budding as compared with tumour bulk were investigated for established EMT signatures, consensus molecular subtype (CMS), gene set enrichment and pathway analysis.A total of 296 genes were differentially expressed with an FDR <0.05 and a twofold change between tumour bulk and budding regions. Genes that were upregulated in the budding signature were mainly involved in cell migration and survival while downregulated genes were important for cell proliferation. Supervised clustering according to an established EMT gene signature categorised budding regions as EMT-positive, whereas tumour bulk was considered EMT-negative. Furthermore, a shift from CMS2 (epithelial) to CMS4 (mesenchymal) was observed as tumour cells transit from the tumour bulk to the budding regions.Tumour budding regions are characterised by a phenotype switch compared with the tumour bulk, involving the acquisition of migratory characteristics and a decrease in cell proliferation. In particular, most tumour budding signatures were EMT-positive and switched from an epithelial subtype (CMS2) in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells.
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Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.
2023-12-08 | PXD037670 | Pride
Project description:Purpose: The goal of this study is to determine whether ectopic expression of the GLI2 transcription factor in the human pancreatic cancer cell line, YAPC is sufficient to cause gene expression changes associated with a EMT switch. Methods: RNA was isolated from YAPC cells engineered to express a doxycycline inducible cassette for ectopic expression of GLI2 following treatment with 1ug/ml of Dox for 6 days. Control YAPC cells expressing an "empty vector" dox inducible cassette were similarly treated for 6 days with 1ug/u Dox and RNA was collected. Three biologically destinct replicates were submitted for library preparation and RNA-sequencing on an Illumina hiseq 2000. The sequence reads that passed quality filters were analyzed at the transcript level using TopHat followed by Cufflinks. qRT–PCR validation was performed using SYBR Green assays Results: RNA-seq data confirmed stable over-expression of GLI2 in the YAPC-rtta-GLI2 cells and not in the EV control cells treated with Dox. Target genes of interest were validated by qRT–PCR. RNA-seq data had a linear relationship with qRT–PCR for all target genes tested. Gene set enrichment analysis of differentially expressed genes showed enrichment of EMT associated pathways which was further validated using functional assays. In addition a statistically significant alteration in SPP1 transcript was discovered in GLI2 overexpressing cells which formed the basis of ongoing experiments in the study. Conclusions: Our data support a role for GLI2 in regulation of genes associated with basal-like subtype switching including SPP1
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Project description:Ribosomes have long been thought of as homogeneous macromolecular machines, but recent evidence suggests they are heterogeneous and could be specialised to regulate translation. Here, we have isolated ribosomal complexes and characterised their protein content across 4 tissues of Drosophila melanogaster via TMT-MS. We find that testes and ovaries contain the most heterogeneous ribosome populations, which occurs through a combination of ribosomal protein paralog-enrichment and ribosomal protein paralog-switching. We have also solved structures of ribosomes isolated from tissues by cryo-EM, revealing differences in precise ribosomal arrangement for testis and ovary 80S ribosomes. Differences in the amino acid composition of paralog pairs and their localisation on the ribosome exterior indicate paralog-switching could alter the ribosome surface, enabling different proteins to regulate translation. One testis-specific paralog-switching pair is also found in humans, suggesting this is a conserved site of ribosome heterogeneity. Overall, this work allows us to propose that mRNA translation might be regulated in the gonads through ribosome heterogeneity, providing a potential means of ribosome specialisation.
2021-07-22 | PXD026227 | Pride
Project description:Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARg are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3 and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remains unknown. Result: We determine the genome-wide transcriptome, enhancer landscape and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion: In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
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