Disrupting ß-catenin dependent Wnt signaling activates an invasive gene program predictive of colon cancer progression
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ABSTRACT:
PROVIDER: PRJNA534423 | ENA |
REPOSITORIES: ENA
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Project description:The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the long-standing understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we lower the levels of Wnt signaling in SW480 and SW620 colon cancer cell lines via interference with two different steps in Wnt signaling that lie upstream or downstream of the effector protein ß-catenin. We find that these Wnt-reduced lines exhibit a more aggressive disease phenotype, including increased mobility in vitro and localized invasion in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion. We identify a set of upregulated genes common among the Wnt perturbations, and find that elevated expression of these genes is strongly predictive of poor patient outcomes in early-invasive colon cancer. These genes may have clinical applications as either patient biomarkers or new drug targets to be used in concert with existing therapies.
2019-12-31 | GSE130236 | GEO
Project description:We define a pathogenic role for a ß-catenin-activated genetic pathway in murine renal dysplasia. Cre-mediated stabilization of ß-catenin in the ureteric cell lineage prior to the onset of kidney development increased ß-catenin levels and caused renal aplasia or severe hypodysplasia. A genome-wide analysis of mRNA expression in dysplastic tissue identified down-regulation of genes required for ureteric branching and up regulation of Tgfß2 and Dkk1. Hoxb7-Cre:EGFP mice ( Zhao, et al. (2004) Dev Biol 276:403-415) were crossed with mice containing loxP sites flanking exon 3 of the ß-catenin allele (ß-catdelta3/delta3) (Harada,et al. (2002) Cancer Res 62:1971-1977) to generate ß-catenin gain-of-function mutant mice specific to the uteric bud, termed ß-catGOF-UB .Eighteen ß-catGOF-UB mutant kidneys and 9 WT kidneys were micro-dissected at E12.5. Mutant kidneys were divided into three random pools (n=3) consisting of 6 kidneys each and mRNA expression assessed by microarray.
2011-03-28 | E-GEOD-20325 | biostudies-arrayexpress
Project description:We define a pathogenic role for a ß-catenin-activated genetic pathway in murine renal dysplasia. Cre-mediated stabilization of ß-catenin in the ureteric cell lineage prior to the onset of kidney development increased ß-catenin levels and caused renal aplasia or severe hypodysplasia. A genome-wide analysis of mRNA expression in dysplastic tissue identified down-regulation of genes required for ureteric branching and up regulation of Tgfß2 and Dkk1.
2011-03-28 | GSE20325 | GEO
Project description:Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation.
2019-02-22 | GSE66848 | GEO
Project description:Hematopoietic stem cells (HSCs) are characterized by their ability to give rise to all mature blood lineages and to renew themselves. Despite their potential for the therapeutic use in cell replacement therapy, the cell fate decisions of HSCs controlled by extrinsic and intrinsic mechanisms remain poorly understood. In summary, our results provide a number of novel and important observations illustrating and enlightening the importance of ß-catenin in hematopoiesis. Specifically, we show that ß-catenin plays an essential role in the immortalization of HSCs. Keywords: hematopoietic stem cells , immortalization, ß-catenin, genetic modification, time course
2006-12-06 | GSE6424 | GEO
Project description:The Wnt/ß-catenin pathway is orchestrating the development of the blood-brain barrier (BBB), but its downstream mediators have remained elusive. To identify potential effectors, we generated an endothelial cell specific Axin1 over-expressing mouse model, AOEiEC. We found that in AOEiE mice Wnt/ß-catenin signalling was down regulated leading to premature regression and remodelling without directly compromising BBB integrity. Interestingly, by comparing transcriptomes of endothelial cells from control and AOEiEC mice, we identified Adamtsl2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the cerebral vasculature during development. Importantly, loss-of-function and gain-of-function experiments revealed that Adamtsl2 alone was sufficient to rescue CNS vascular defects seen upon Wnt-signalling inhibition. Furthermore, using various cell and animal models we demonstrate that Adamtsl2 exerts its function by fine-tuning the TGFβ signalling pathway in CNS vessels. In conclusion, this study implicates Adamtsl2 as a mediator of Wnt/ß-catenin signalling during BBB development by linking it to TGFβ signalling.
2019-01-31 | GSE77874 | GEO
Project description:Focal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in otherwise normal liver. In contrast, FNH-like nodules occur in cirrhotic liver but share similar histopathological features. To better understand the pathophysiology of FNH, we performed a transcriptomic analysis. Methods: Affymetrix and cDNA microarrays were used to compare gene expression in eight FNHs with that in tissue from six normal livers. Selected genes were validated with quantitative RT-PCR in 70 benign liver tumors including adenomas and cirrhotic and FNH-like lesions. Results: Among the deregulated genes in FNHs, 19 were physiologically zonated in the normal liver lobule. All six periveinous genes were up-regulated in FNH, whereas 13 genes normally expressed in the periportal area were down-regulated. Immunohistochemistry revealed that glutamine synthetase was markedly overexpressed, forming anastomosed areas usually centered on visible veins. ß-catenin mRNA was slightly but significantly overexpressed, as were several known ß-catenin target genes. Moreover, activated hypophosphorylated ß-catenin protein accumulated in FNH in the absence of activating mutations. These results suggest zonated activation of the ß-catenin pathway specifically in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of ß-catenin expression. Conclusions: In FNH, increased expression of the ß-catenin pathway was restricted to enlarged periveinous areas, which may explain the slight polyclonal over-proliferation of hepatocytes at the origin of the lesion. FNH-like nodules may have a different pathogenetic origin. Keywords: Disease state analysis
2008-06-18 | GSE9536 | GEO
Project description:HCT116 colorectal cancer cells were treated with a novel inhibitor of ß-catenin/BCL9 interaction and evaluated for transcriptional changes using RNA-seq.
2022-01-01 | GSE182086 | GEO
Project description:De novo acquisition or subclonal selection of chemotherapy resistant cell populations are at the base of relapse in cancer. We have now investigated the role of ß-catenin in the evolution of T-ALL patients. We identified an RNA-processing signature that is directly regulated by ß-catenin in T-ALL cell lines. This signature was sufficient to identify T-ALL patients with poorest prognosis, together with high ß-catenin levels in an outdated discovery cohort with high incidence of refractory patients. In an independent validation cohort of T-ALL patients treated with current protocols and a 5-years survival >90%, neither ß-catenin-dependent signatures nor ß-catenin mRNA levels were predictive of patient outcome. However, further analysis of data demonstrated the prognosis value of the ß-catenin RNA-processing signature specifically in tumors carrying high BRCA1 levels. Finally, we show that both ß-catenin and BRCA1 enhanced the recovery of T-ALL cells after chemotherapy thus providing a mechanistic explanation for the prognosis value of ß-catenin and BRCA1.
2022-12-12 | GSE196985 | GEO
Project description:De novo acquisition or subclonal selection of chemotherapy resistant cell populations are at the base of relapse in cancer. We have now investigated the role of ß-catenin in the evolution of T-ALL patients. We identified an RNA-processing signature that is directly regulated by ß-catenin in T-ALL cell lines. This signature was sufficient to identify T-ALL patients with poorest prognosis, together with high ß-catenin levels in an outdated discovery cohort with high incidence of refractory patients. In an independent validation cohort of T-ALL patients treated with current protocols and a 5-years survival >90%, neither ß-catenin-dependent signatures nor ß-catenin mRNA levels were predictive of patient outcome. However, further analysis of data demonstrated the prognosis value of the ß-catenin RNA-processing signature specifically in tumors carrying high BRCA1 levels. Finally, we show that both ß-catenin and BRCA1 enhanced the recovery of T-ALL cells after chemotherapy thus providing a mechanistic explanation for the prognosis value of ß-catenin and BRCA1.
2022-12-12 | GSE180650 | GEO