Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA305551 | ENA |
REPOSITORIES: ENA
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Project description:Cancer progression and wound healing share some characteristics. Most colorectal cancers are differentiated adenocarcinomas that maintain three-dimensional structures to some extent. Hence, disruption of the architecture can provoke remodeling similar to the remodeling of normal intestinal epithelium. We used our recently developed three-dimensional culture system to investigate the response of cancer cell spheroids to mechanical disruption. Specifically, we developed a protocol for homogenous disruption of the spheroids that maintained the cell-cell contacts. After disruption, 9 spheroids from 9 patient samples reformed within a few hours, and 2 showed accelerated spheroid growth. Stemness increased after spheroid disruption, as assessed by marker expression, spheroid forming capacity, radiation sensitivity, and tumorigenesis. The spheroid-forming capacity increased in 6 of 11 spheroids. The disruption signature, as determined by gene expression profiling, supported the incidence of remodeling and predicted the prognosis of the colorectal cancer patients. WNT and HER3 signaling was increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increases in growth and stemness after disruption. Thus, disorganized architecture in patient tumors might reflect the processes of disruption and subsequent remodeling and represent a cause rather than simply a consequence of malignancy progression. Gene expression in cancer tissue-originated spheroids (CTOSs) was measured at pre, 6 hr, 24 hr, and 4 days after mechanical disruption. One experiment was performed at each time point.
2015-12-10 | E-GEOD-75867 | biostudies-arrayexpress
Project description:Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis.
2016-11-22 | GSE82133 | GEO
Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
2005-09-02 | E-SMDB-1723 | biostudies-arrayexpress
Project description:Cancer progression and wound healing share some characteristics. Most colorectal cancers are differentiated adenocarcinomas that maintain three-dimensional structures to some extent. Hence, disruption of the architecture can provoke remodeling similar to the remodeling of normal intestinal epithelium. We used our recently developed three-dimensional culture system to investigate the response of cancer cell spheroids to mechanical disruption. Specifically, we developed a protocol for homogenous disruption of the spheroids that maintained the cell-cell contacts. After disruption, 9 spheroids from 9 patient samples reformed within a few hours, and 2 showed accelerated spheroid growth. Stemness increased after spheroid disruption, as assessed by marker expression, spheroid forming capacity, radiation sensitivity, and tumorigenesis. The spheroid-forming capacity increased in 6 of 11 spheroids. The disruption signature, as determined by gene expression profiling, supported the incidence of remodeling and predicted the prognosis of the colorectal cancer patients. WNT and HER3 signaling was increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increases in growth and stemness after disruption. Thus, disorganized architecture in patient tumors might reflect the processes of disruption and subsequent remodeling and represent a cause rather than simply a consequence of malignancy progression.
2015-12-10 | GSE75867 | GEO
Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells. Groups of assays that are related as part of a time series. Computed
2005-09-10 | E-GEOD-3282 | biostudies-arrayexpress
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress
Project description:Elucidating the interactions between the adhesive and transcriptional functions of beta-catenin in normal and cancerous cells.
van Leeuwen IM1, Byrne HM, Jensen OE, King JR.
Author information
1
Centre for Mathematical Medicine and Biology, Division of Applied Mathematics, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK. pmzivl@exmail.nottingham.ac.uk
Abstract
Wnt signalling is involved in a wide range of physiological and pathological processes. The presence of an extracellular Wnt stimulus induces cytoplasmic stabilisation and nuclear translocation of beta-catenin, a protein that also plays an essential role in cadherin-mediated adhesion. Two main hypotheses have been proposed concerning the balance between beta-catenin's adhesive and transcriptional functions: either beta-catenin's fate is determined by competition between its binding partners, or Wnt induces folding of beta-catenin into a conformation allocated preferentially to transcription. The experimental data supporting each hypotheses remain inconclusive. In this paper we present a new mathematical model of the Wnt pathway that incorporates beta-catenin's dual function. We use this model to carry out a series of in silico experiments and compare the behaviour of systems governed by each hypothesis. Our analytical results and model simulations provide further insight into the current understanding of Wnt signalling and, in particular, reveal differences in the response of the two modes of interaction between adhesion and signalling in certain in silico settings. We also exploit our model to investigate the impact of the mutations most commonly observed in human colorectal cancer. Simulations show that the amount of functional APC required to maintain a normal phenotype increases with increasing strength of the Wnt signal, a result which illustrates that the environment can substantially influence both tumour initiation and phenotype.
2020-01-09 | MODEL2001090001 | BioModels
Project description:The MSI2 RNA binding protein has recently emerged as a potent oncogene playing key roles in hematopoietic stem cell homeostasis and malignant hematopoiesis. Here we demonstrate that MSI2 is expressed in the intestinal stem cell compartment, that its expression is elevated in colorectal adenocarcinomas, and that MSI2 loss of function abrogates colorectal cancer cell growth. We thus examined the oncogenic consequences of MSI2 gain of function in the intestinal epithelium with a drug inducible mouse model. Strikingly, MSI2 induction alone was sufficient to phenocopy the majority of morphological and molecular consequences of acute loss of the APC tumor suppressor in the intestinal epithelium. We demonstrate that this phenotype is independent of both the activation of the other oncogenic Musashi family member, Msi1, and of canonical Wnt pathway activation. Transcriptome-wide RNA-binding analysis indicates that MSI2 acts as a pleiotropic inhibitor of known intestinal tumor suppressors including Lrig1, Bmpr1a, Cdkn1a, and Pten. Finally, we demonstrate that inhibition of the PDK-AKT-mTORC1 axis downstream of Pten rescues oncogenic consequences of MSI2 induction. Taken together, our findings identify MSI2 as a central component in an unappreciated oncogenic pathway promoting intestinal transformation. 2 wild-type samples, 2 TRE-Msi2 samples
2014-12-20 | E-GEOD-64388 | biostudies-arrayexpress
Project description:The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF-family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium using tissue-specific, inducible beta-catenin gene ablation in adult mice. Block of Wnt/beta-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of beta-catenin resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture micro dissection confirmed those observations and allowed to identify genes potentially responsible for the functional preservation of intestinal stem cells. Experiment Overall Design: laser capture microdissection of intestinal crypts, control vs. beta-catenin mutant (2days after induction of deletion by tamoxifen), two rounds of amplification of mRNA
2008-06-16 | E-GEOD-8818 | biostudies-arrayexpress
Project description:Somatic DNA alteration underlies tumor development and progression, and gives rise to tumors with diverse genetic contexts. Here, we identify in a collection of 29 colorectal cancer cell lines and 226 primary colorectal tumors recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor CDX2, a master regulator of anterior-posterior patterning, midgut development, and intestinal epithelial cell differentiation and maintenance. In contrast to its described role as a colorectal tumor suppressor, we show that in the context of genomic amplification, CDX2 is required for proliferation and anchorage-independent growth of colorectal cancer cells. By genome-wide expression and location analysis, we reveal that CDX2 directly promotes expression of Wnt pathway genes. Further results suggest that CDX2 induces expression of intestinal differentiation markers and modulates b-catenin transcriptional activity. These data characterize CDX2 as a novel lineage-survival oncogene deregulated in colorectal cancer. comparative genomic hybridization by array
2012-11-02 | E-GEOD-29953 | biostudies-arrayexpress