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97dd9532-0482-4bf1-ad1d-fb976b8ed7ea - samples

ABSTRACT: This dataset contains whole-genome sequencing data files from colon organoid cultures, which were mutated using CRISPR-Cas9 for specific genes (APC, KRAS, TP53 and SMAD4) to generate in vitro transformed cancer cells. After introducing each mutation, the resulting cultures were subjected to whole-genome sequencing. In addition, some cultures were xenotransplanted in recipient mice. The resulting primary tumors and corresponding metastases were subjected to whole-genome sequencing.

PROVIDER: EGAD00001002719 | EGA |

REPOSITORIES: EGA

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The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy.

Ahn Sung-Min SM Ansari Adnan Ahmad AA Kim Jihun J Kim Deokhoon D Chun Sung-Min SM Kim Jiyun J Kim Tae Won TW Park Inja I Yu Chang-Sik CS Jang Se Jin SJ

Oncotarget 20161001 42

Early-onset colorectal cancers (EOCRCs) may have biological or genomic features distinct from late-onset CRCs (LOCRCs). Previous studies have mostly focused on the germline predisposition conditions of EOCRCs, but we hypothesized that EOCRCs may have distinct somatic aberrations that accelerate cancer development. To identify the somatic aberrations that accelerate cancer development at an early age, we conducted whole exome sequencing for 28 polyposis-unrelated, microsatellite stable (MSS) EOCR ...[more]

PMID: 27612425

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Whole genome sequencing of colon organoid cultures with artificially induced oncogenic mutations

Project description:Using the CRISPR-Cas9 genome editing system, various oncogenic mutations were introduced in the genome of normal adult stem cells derived from the colon. The resulting clonal cultures were subjected to whole genome sequencing. In addition, the cultures were transplanted in a mouse and the resulting primary and metastatic tumors were also subjected to whole genome sequencing. The initial bulk culture, which was used to generate the mutations, was also whole genome sequenced and served as a reference sample to filter germline variants.

| EGAS00001001969 | EGA

mRNA expression data from adenoma, gene modified, and colorectal cancer organoid.

Project description:We established human colorectal tumor organoids from benign adenoma, primary colorectal cancer or metastasized colorectal cancer. The gene signature of tumor organoids associated with their tumor progression status. We also generated genome-edited organoids from human intestinal organoids recapitulating adenoma-carcinoma sequence. Gene expression signature of the genome engineered organoids were similar to that of adenoma organoids. This result indicated multiple (up to five) genetic mutations were insufficient for gene expression reprogramming of colorectal cancer. We used microarrays to detail the global program of gene expression in human colorectal tumor organoids and artificially mutation introduced organoids. To assess the expression profiling of genome-engineered organoids, we prepared total-RNA from cultured adenoma, carcinoma and genome-engineered organoids. We produced two types of genome-engineered organoids using the CRISPR/Cas9 or lentivirus vector system. Each engineered gene and engineered methods are described as a single alphabet and method name, respectively, in the sample characteristics field. The abbreviations for the engineered genes are as follows. 1) Genome-engineered organoids with CRISPR/Cas9 A = APC deletion; K = KRAS G12V knock in; S = Smad4 deletion; T = TP53 deletion; P = PIK3CA E545K knock in. 2) Genome-engineered organoids with Lent virus vector B = CTNNB1 S33Y overexpression; K = KRAS G12V overexpression; S = Smad4 shRNA overexpression; T = TP53 shRNA overexpression; P = PIK3CA E545K overexpression.

2015-01-18 | E-GEOD-57965 | biostudies-arrayexpress

Dissecting the functional selectivity of TGFβ signaling pathway components using genome engineered human organotypic skin models

Project description:Transforming growth factor β (TGFβ) signaling is essential in cell growth and differentiation. Yet, the role of the individual TGFβ signaling components in human tissue homeostasis and transformation is still incompletely understood. Here we dissected the importance of the core components in the TGFβ signaling pathway by CRISPR/Cas9 genome editing of human keratinocytes. The edited keratinocytes were used for human organotypic skin cultures and global quantitative proteomics and phosphoproteomics by mass spectrometry. Characterization of cells and human organotypic skin tissues showed control of epithelial differentiation by Smad4-dependent TGF signaling through cell cycle regulation and ECM expression. In contrast, we found that the combined Smad4 dependent and independent pathways, governed by TGFβRII, controls epithelial homeostasis and prevents invasive growth by blocking epithelial inflammation and activation of p38 and ERK signaling. The study provides a framework for exploration of signaling pathways in human 3D tissue models and with global phosphoproteomics.

2023-02-09 | PXD024935 | Pride

Transcription profiling by array of cis-Apc+/Delta716/Smad4+/- mouse liver vs C57BL/6N mouse liver

Project description:cis-Apc+/Delta716/Smad4+/- mice spontaneously develop multiple invasive intestinal carcinomas due to loss of heterozygosity and manifest symptoms associated with cancer cachexia within four months of age. To investigate the role of the liver in cachexia pathophysiology, we compared the transcriptomes of cachexia and control mouse livers. We isolated total RNA from livers of four C57BL/6N mice and four cis-Apc+/Delta716/Smad4+/- mice. Total RNA samples were then employed to perform microarray analysis (Agilent SurePrint G3 Mouse GE 8x60K Microarray).

2023-08-04 | E-MTAB-11771 | biostudies-arrayexpress

USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating B-catenin deu

Project description:The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRC) resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations, thus can be used as tumor-specific therapeutic target for most CRCs.

2017-11-09 | PXD007947 | Pride

Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.

Project description:In colorectal cancer, the role of the most common driver mutations in APC, KRAS, SMAD4 and TP53, on global mRNA translation are incompletely understood. To adress this, we generated and characterised mouse intestinal organoid models with oncogenic mutations in each of these genes using Cre-Lox recombination in ex vivo organoid cultures combined with stable expression of short hairpin RNAs. Microarray analysis was used to characterise transcriptomic reprogramming that supports altered global translation rates in mutant cells.

2020-05-31 | GSE143509 | GEO

Transcription profiling by array of Apc+/Delta716 mouse intestinal polyps vs normal intestinal mucosa

Project description:The APC (Adenomatous Polyposis Coli) gene encodes a large multidomain protein that plays an integral role in the Wnt/beta-catenin signaling pathway. The loss-of-function mutation in APC is considered the earliest genetic alteration in the course of adenoma-carcinoma sequence of colorectal cancer progression, and the resulting constitutive activation of Wnt/beta-catenin signaling is required for the maintenance of advanced colorectal cancer. In order to identify genes affected by loss of Apc function, we performed transcription profiling of mouse small intestinal tissues comparing polyps with normal mucosa of Apc+/Delta716 mice. We isolated total RNA from intestinal polyps and normal intestinal mucosa from 3 individual Apc+/Delta716 mice. Total RNA samples were then employed to perform microarray analysis (Agilent Whole Mouse Genome Microarray Ver. 2.0, 4x44K).

2020-11-01 | E-MTAB-9187 | biostudies-arrayexpress

Single cell changes in DBZ or DMSO treated cells derived from Apc-mutant organoid cultures

Project description:We made intestinal organoid cultures from Villin-CreERT2;Apcflox/flox mice. Organoids were subjected to 4-OH-Tam treatment, whereafter Apc mutant organoids were selected in R-Spondin free medium. DBZ or DMSO treatment was started on day 3. On day 8, organoids were dissociated to obtain single cells and analyzed using the Chromium Single-cell 3'RNA-sequencing system

2018-08-21 | GSE118055 | GEO

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [scRNA-seq]

Project description:We thought the immediate effects of APC inactivation may represent unexplored therapeutic vulnerabilities in later stages of advanced colorectal adenocarcinoma. We performed transcriptome profiling of epithelial colon organoids immediately after APC inactivation and cross-referenced gene expression changes to the transcriptomes of several mouse models of colon cancer, including colon tumors in an inflammation-induced CRC model (AOM-DSS), a model of familial adenomatous polyposis (FAP, the Apcmin mouse), and an implantation-based model of metastatic adenocarcinoma using Apc/Trp53/KrasG12D/Smad4 quadruple-mutant tumor organoids15 (APKS tumoroids). Of the roughly 150 genes whose expression is acutely induced upon APC loss and remains elevated in these colon cancer models.

2022-12-31 | GSE198758 | GEO

The intestinal adenocarcinomas of the cis-Apc/Smad4 compound mutant mice

Project description:Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using the cis-Apc/Smad4 mutant mice, a model of invasive colorectal cancer whose TGF-beta family signaling is blocked, we demonstrate here that a novel type of immature myeloid cells (iMCs) is recruited from the bone marrow to the tumor invasion front. These CD34+ iMCs express MMP9/2 and CC-chemokine receptor 1 (CCR1), and migrate toward its ligand CCL9. In the adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. Such changes in the chemokine expression or the CD34+ iMC recruitment are not observed in the Apc (+/–) mice, a model of adenomatous polyposis. By knocking out Ccr1 gene in the cis-Apc/Smad4 mutant mice, we further demonstrate that lack of CCR1 prevents the accumulation of CD34+ iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of the TGF-beta family signaling in tumor epithelium causes accumulation of iMCs that help tumor invasion. Keywords: disease state analysis

2007-04-25 | GSE6950 | GEO

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