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

ABSTRACT: AKT dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype

PROVIDER: PRJNA561767 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10021974.fastq.gz	Fastqsanger.gz
	SRR10021975.fastq.gz	Fastqsanger.gz
	SRR10021976.fastq.gz	Fastqsanger.gz
	SRR10021977.fastq.gz	Fastqsanger.gz
	SRR10021978.fastq.gz	Fastqsanger.gz

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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 [2015]

2020-07-29 | GSE136254 | GEO

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

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

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

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

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

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A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (ChIP-seq)

Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma

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A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (RNA-Seq)

Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma

2018-12-28 | GSE124429 | GEO

NOTCH3 Promotes Malignant Progression of Bladder Cancer by Directly Regulating SPP1 and Activating PI3K/AKT Pathway

Project description:The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1(SPP1), a potential downstream target gene of NOTCH3，by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA.

2024-11-27 | GSE279910 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-29 | GSE136257 | GEO

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer.

Project description:Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of 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 tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

| S-EPMC7537393 | biostudies-literature

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