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B-catenin deficiency, but not c-Myc deletion, suppresses the immediate phenotypes of Apc loss in the liver

ABSTRACT: Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE65476 | GEO | 2015/01/31

SECONDARY ACCESSION(S): PRJNA274133

REPOSITORIES: GEO

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B-catenin deficiency, but not c-Myc deletion, suppresses the immediate phenotypes of Apc loss in the liver

Project description:Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver. Samples were collected from Genetcially modified mice of the genotypes indicated in the characteristics field. Gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss, cMYC loss and combined APC and cMYC loss in the liver (and compared to matched control samples in which the genes were not recombined).

2015-01-31 | E-GEOD-65476 | biostudies-arrayexpress

Bcl9 and Pygo synergize downstream of Apc to effect intestinal neoplasia in mouse models recapitulating Familial Adenomatous Polyposis (Illumina Beadchip)

Project description:Bcl9 and Pygo function within the Wnt enhanceosome to effect β-catenin-dependent transcription. Whether they also mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumorigenesis initiated by Apc loss-of-function (ApcMin). Gene expression profiling revealed that loss-of-Bcl9 synergizes with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages.

2018-12-31 | GSE121130 | GEO

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

Transcriptome changes following loss of Apc in the intestine

Project description:Nearly all colorectal cancers have dysregulated Wnt signalling, predominantly through the mutation of the Apc (Adenomatous Polyposis Coli) gene. Therefore it is of vital importance to elucidate the key Wnt target genes in intestinal cells in vivo. We have used a novel inducible cre-lox based murine system (designated ApcFlox) to investigate the consequences of perturbation of Wnt signalling following inactivation of Apc in vivo within 100% of the intestinal epithelium. We have employed microarray analysis at 3 time points within our ApcFlox system (Day 3 prior to the onset of phenotype, day 4 the establishment of the phenotype and day 5 gross phenotype of altered proliferation, differentiation and migration) and from adenomas arising in the ApcMin/+ background allowing us characterise Wnt/beta-catenin target genes based on their expression profiles during different stages of intestinal tumourigenesis. Furthermore, we have employed microarray analysis using livers from our ApcFlox system and have demonstrated that there is very little overlap in the Wnt target genes induced by Apc loss in the liver and the intestine. More importantly, we have been able to determine a novel set of putative Wnt/beta-catenin target genes which are upregulated at both early and late stages of tumourigenesis in the intestine and may represent novel therapeutic targets in colon cancer. Samples were collected from Genetcially modified mice of the genotypes indicated on the sample records. Where appropriate, gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss in the small intestine at three time points (and compared to matched control samples in which the gene was not recombined). Furthermore, these samples were compared to colonic polyps (and normal colon) taken from the Apcmin Mouse.

2015-01-31 | E-GEOD-65461 | biostudies-arrayexpress

Hepatocyte identity and zonal position determine tumourigenic potential of mutant β-catenin

Project description:Oncogenic mutations in otherwise normal tissue are common in many adult tissues. This suggests multiple events need to converge to drive tumourigenesis and that many processes such as tissue differentiation may be protective against carcinogenesis. Within the liver Wnt/β-catenin signalling maintains zonal differentiation during liver homeostasis. However, the CTNNB1 oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant Wnt signalling that promotes cell growth. Here we investigated the antagonistic interplay between Wnt-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. In a model that acutely recombined mutant Wnt (Ctnnb1-ex3) and MYC alleles, we found that β-catenin mutants transiently stimulated growth in zone-1 and -2 hepatocytes within the Wnt-low region of the liver lobule – before inducing a differentiated zone-3 fate. To investigate the role of translation in this model of wnt and myc driven growth we performed Ribosome sequencing of whole liver at the early proliferative stage and the later differentiated stage. We found that Mutamt B-Catenin and MYC livers had a unique tanslational efficiency , which promted translation of RNA transcripts associated with growth.

2024-09-12 | GSE275864 | 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

Cooperation of MYC and b-catenin in liver tumorigenesis requires Yap/Taz

Project description:One of the transcriptional targets of b-catenin/TCF and a key downstream effector of the WNT/b-catenin pathway in several tissues is the MYC proto-oncogene, which encodes for a transcription factor that is a master regulator of proliferation- and growth-related genes. However, several evidences indicate that this epistatic relationship does not seem to occur in liver: indeed Myc was not induced upon b-catenin activation driven by APC loss, and Myc deletion in hepatocytes does not suppress the effects of APC loss on cell proliferation and liver zonation. Besides, there are indications that the two pathways can be independently activated, and cooperate during tumorigenesis. In particular, MYC amplification and b-catenin mutations showed a tendency toward co-occurrence in either adult HCC or aggressive childhood hepatoblastoma, and MYC-driven HCC in experimental mouse models frequently acquired activating mutations in b-catenin. In order to address whether these observations reflect a functional cross-talk between the two pathways that may occur in a specific molecular subgroup of HCC patients, we generated a new mouse model allowing conditional activation of MYC and -catenin in hepatocytes. This model demonstrated a strong cooperativity between the two oncogenes in promoting liver tumorigenesis. Our data indicate that this cooperation occurs mainly through unrestrained proliferation of liver cells that requires the activity of the transcriptional co-factors Yap and Taz.

2020-05-12 | GSE138296 | GEO

Transcriptome changes following loss of Apc in the intestine

2015-01-31 | GSE65461 | GEO

The impact of P53 loss on transcriptome changes following loss of Apc in the intestine

Project description:BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of beta-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development. Samples were collected from genetically modified mice. Gene recombination was induced using IP administration of beta-napthoflavone.

2015-06-25 | E-GEOD-70262 | biostudies-arrayexpress

Mouse hepatoblastoma models with expression of mutant β-catenin and/or c-Myc for therapeutic target identification of childhood liver cancer

Project description:Hepatoblastoma (HB), the most common type of pediatric liver cancer, is associated with aberrant wnt/β-catenin activation and Myc amplification/overexpression. Mice expressing both alleles developed HBs and HCCs with incomplete penetrance by 5-6 weeks of age with fetal and mixed fetal/embryonal HBs, the most prevalent histologic HB subtypes seen in children being the predominant tumor types. To address the roles of mutant wnt/β-catenin activation and Myc over-expression in the pathogenesis of HB, c-Myc and mutant dominant-stable β-catenin were co-targeted to immature cells of the developing mouse liver.

2017-08-23 | GSE79084 | GEO

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