Functional studies of TP63-affected ESCC tumor immune microenvironment
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ABSTRACT:
PROVIDER: PRJNA916887 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22937978.fastq.gz | Fastqsanger.gz | |||
| SRR22937979.fastq.gz | Fastqsanger.gz |
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Project description:Our preliminary data from unbiased analyses of both ESCC patient samples and cell lines identified interferon-γ (IFN-γ) signaling pathway as the most significantly enriched pathways suppressed by TP63. To validate the activation of IFN pathways and the immune responses upon silencing of TP63, we utilized immune-competent mice to conduct allograft experiments. To analyze the effect of TP63 on ESCC tumor microenvironment, resected tumors were then collected to perform scRNA-seq.
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Project description:Genomics studies have detected numerous genetic alterations in esophageal squamous-cell carcinoma (ESCC), a highly malignant and leading mortal cancer. However, the functions of these mutations in the formation and progression of ESCC largely remain elusive, partially due to lack of feasible animal models. Here, we report a convenient platform with normal esophageal organoids, CRISPR/cas9-mediated introduction of ESCC-associated genetic alterations, and orthotopic transplantation to generate a serial of primary ESCC models in mice. With this platform, we validated that multiple frequently mutated genes, including FAT1/2/4, NOTCH2, KMT2D, EP300, and TGFBR2, as bona fide tumor suppressor genes in ESCC. Among them, TGFBR2 loss dramatically promoted tumorigenesis and multi-organ metastasis. Paradoxically, TGFBR2 deficiency led to Smad3 activation and disruption of Smad3 could partially restrain the progression of Tgfbr2 mutated tumors. Drug screening with tumor organoids revealed that pinaverium bromide, a calcium channel blocker used for irritable bowel syndrome, could repress Smad3 activity and restrain Tgfbr2 deficient ESCC in vitro and in vivo. Our studies provide a highly efficient platform to investigate the in vivo functional of ESCC-associated mutations and develop potential treatment for this miserable malignancy.
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Project description:To understand the difference of protein expression between paired esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues, we collected 10 paired ESCC and normal tissues from surgical resected specimems for high-throughput proteomic experiments. From comparative analysis, the dysregulated signaling pathways in ESCC could be uncovered.
2020-08-11 | PXD019834 | Pride
Project description:To discover ESCC related proteins, we used SWATH to quantify the protein abundance between ESCC and adjacent tissues. Briefly, we pooled 10 ESCCtissues and their corresponding adjacent tissues for SWATH acquisition with three replicates.Three DDA repeats were also acquired with the pooled 10-paired ESCC tissue.The trypsin digested peptide mixture was analyzed by AB SCIEX 5600 (AB SCIEX).The database searching procedure was achieved using ProteinPilot v4.5 (AB Sciex). The database is IPI_homo_sapiens_V3.87.
2015-09-22 | PXD001764 | Pride
Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC should improve identification of risk factors in molecular subtypes and provide potential targets for early detection and therapy. To better characterize molecular changes in ESCC, we followed up a previous cDNA array study with additional discovery and confirmatory studies in new ESCC cases using alternative methods. We profiled global gene expression (Affymetrix U133A/B chip) for discovery and confirmation, and validated selected dysregulated genes with additional RNA (qRT-PCR, N=51) or protein studies (immunohistochemistry [IHC] of tumor tissue microarray [TMA], N=275).We also found genes associated with survival. The dysregulated genes should aid in identifying risk factors in ESCC, as well as potential targets for early detection, and outcome prediction and therapy. 53 ESCC samples and 53 matched normal samples were analyzed (samples AE43 and AE45 were not run on HG-U133B due to not having enough material). Contributors have chosen not to include the clinical phenotypes in their GEO submission.
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Project description:Purpose: To identify TP63 expression regulated pathways in HNSCC Methods: A recombinant lentivirus encoding either NS shRNA or TP63 shRNA was introduced into a HNSCC cell line, FaDu. SCCs were gene generated by implanting either FaDu-NS shRNA (n=3) or FaDu-TP63 shRNA into the tongue of athymic nude mice. Tongue SCCs harvested at the end of study were used for transcriptome analysis
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Project description:Patients with lymphoma harboring TP63 rearrangements have aggressive clinical course and dismal prognosis with no target therapy available. Thus, there is an urgent need to elucidate the molecular mechanisms and to develop novel therapeutic options for these patients. We then generated a TBL1XR1::TP63 fusion knockin trangenic mouse model and crossed with CD2/iCre mouse. This project is to study the role and function of TP63 fusion in mouse lymphomagenesis.
2023-10-01 | GSE240201 | GEO
Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC should improve identification of risk factors in molecular subtypes and provide potential targets for early detection and therapy. To better characterize molecular changes in ESCC, we followed up a previous cDNA array study with additional discovery and confirmatory studies in new ESCC cases using alternative methods. We profiled global gene expression (Affymetrix U133A/B chip) for discovery and confirmation, and validated selected dysregulated genes with additional RNA (qRT-PCR, N=51) or protein studies (immunohistochemistry [IHC] of tumor tissue microarray [TMA], N=275).We also found genes associated with survival. The dysregulated genes should aid in identifying risk factors in ESCC, as well as potential targets for early detection, and outcome prediction and therapy.
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Project description:Background & Aims: Lineage-specific expression of long non-coding RNAs (lncRNAs) has been observed recently. However, the underlying mechanism of such specific transcription regulation is unclear. The aim of this study is to identify squamous cell carcinoma (SCC) lineage-specific lncRNAs and to investigate the mechanisms for their expression and function. Methods: Expression characteristics and functions of four candidate SCC-specific lncRNAs were explored. qRT-PCR assays were employed to measure the expression of LINC01503 in 113 tumor/normal matched esophageal SCC (ESCC) cases and its association with survival was determined. The mechanisms underlying LINC01503 function and regulation in ESCC cells were examined using molecular biological methods. Results: Using SCC as a model, we identified a novel super-enhancer (SE)-driven lncRNA, LINC01503, which was uniquely expressed in SCCs such as those from esophagus (ESCC) and head and neck (HNSC). LINC01503 was up-regulated in SCCs and its high expression correlated with poor clinical outcomes. SCC master transcriptional factor TP63 directly bound to a SE at LINC01503 locus and activated its transcription. LINC01503 exhibited strong oncogenic functions in ESCC cell models both in vitro and in vivo. ERK2 and EBP-1 were identified as interacting proteins mediating the effects of LINC01503. Specifically, LINC01503 protected ERK2 from dephosphorylation by DUSP-6, leading to the activation of ERK/MAPK pathway. Similarly, LINC01503 interfered the interaction between EBP-1 and PI3K p85, enhancing Akt signaling pathway. Conclusions: These results demonstrated that LINC01503 is a lineage-specific oncogene in ESCC, which may serve as a potential biomarker and therapeutic target for SCC patients.
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