Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Intrinsic WNT pathway hyperactivation dictates metastasis in mesenchymal colorectal cancer

ABSTRACT: Colorectal cancer (CRC) can be divided into 4 distinct subtypes of which consensus molecular subtype 4 (CMS4) is most aggressive and associated with metastasis and poor survival. Previously, we reported that the KPN mouse model, containing a Kras mutation, Trp53 deletion and Notch1 intracellular domain overexpression, resembles human CMS4. Strikingly, although tumor formation in this model is slow and limited in number, effective metastasis is observed pointing to in vivo selection. To understand this aggressive behavior, we compared two distinct in vitro KPN models, organoids and tumoroids. The organoid model represents a system driven by its original mutations, while the tumoroids were derived from in vivo grown tumors that allowed for selection during their development. Here, we reveal that tumoroids harbor endogenous WNT pathway activity driven by tankyrase activity and Cdx2 downregulation. The importance of this WNT pathway activation was evident for metastasis development, but less so for primary tumor growth. Intriguingly, these findings reflect a specific subset of aggressive human CMS4 cancers that display low CDX2 expression and lack of classical WNT pathway mutations, that have a higher tendency to metastasize. Together, these data propose a novel mechanism for WNT pathway hyperactivation that drives metastasis formation in an aggressive CRC model.

ORGANISM(S): Mus musculus

PROVIDER: GSE277663 | GEO | 2025/02/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

AKT dependent Notch3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype

Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

2021-09-08 | PXD014778 | Pride

AKT dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype [2016]

2020-07-29 | GSE136218 | GEO

AKT dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype [2015]

2020-07-29 | GSE136254 | GEO

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses

Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.

2019-02-28 | PXD012650 | Pride

LAKTP_MTO orthotopic primary caecum tumours from Galunisertib-treated C57BL/6J mice

Project description:Mouse tumour organoids (MTOs) derived from a compound mutant (LAKTP) intestinal cancer model were orthoptopically transplanted into syngeneic C57BL/6J mice. Tumour-bearing mice were treated with TGF-beta inhibitor Galunisertib or vehicle control. Whole tumour mRNA was extracted from primary tumours and expression profiling was performed with the objective to characterize the tumour microenvironment (TME). As a TGF-beta-activated TME has been associated to a poor prognosis and the CRC consensum molecular subtype CMS4, and the mouse model was found to have such an activated TME, we used the array data to classify these tumours in this mouse model system as CMS4-like. Furthermore, treatment with TGF-beta inhibitor reduced the fibroblast- and T cell-specific TGF-beta response signatures, also associated to poor prognosis in human CRC. This treatment was associated to a strong reduction/prevention of liver metastasis, as well as a reduction of primary tumour (and local carcinomatosis) size.

2018-02-12 | GSE103562 | GEO

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses II

Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed comprehensive transcriptome and proteome profiling in human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal colon stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.

2019-02-11 | GSE125578 | GEO

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses

Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed comprehensive transcriptome and proteome profiling in human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal colon stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.

2019-02-11 | GSE125472 | GEO

KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer

Project description:Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of β-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of β-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of β-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between β-catenin and ZNT9, thereby leading to decreased β-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/β-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.

2022-08-19 | GSE205547 | GEO

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Project description:Peritoneal metastases (PM) in colorectal cancer (CRC) present a significant challenge due to limited treatment options and poor patient prognosis. While cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) offers curative potential for selected patients, its overall benefit remains limited compared to surgery alone. In this study we show that the majority of CRC-PM represent the CMS4-subtype. Despite CRS-HIPEC treatment, CMS4 patients had high rates of recurrent disease and mortality, indicating limited effectiveness of the treatment. To explore alternative treatment approaches, we queried large-scale compound screens and discovered the copper (Cu)-ionophore elesclomol (ES) as a highly effective agent against CMS4-specific disease models. ES exhibited rapid and selective cytotoxicity against CMS4 cells by targeting the oxidative phosphorylation machinery. CMS4 cells had reduced absolute mitochondrial content and lower expression of genes involved in oxidative phosphorylation, making them vulnerable to ES-induced cytotoxicity. Short exposures to ES combined with Cu (ES-Cu) resulted in near-complete growth inhibition of cancer cells, suggesting its potential for HIPEC-like intra-abdominal treatment procedures. Furthermore, ES-Cu demonstrated efficacy in preclinical models of PM, including CRC-PM and ovarian cancer organoids, and a HIPEC rat model of PM. These findings highlight ES-Cu as promising candidate for the local treatment of CRC-PM, with broader implications for other cancer types characterized by high incidence of PM.

2024-05-01 | GSE242676 | GEO