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APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [bulk RNA-seq]

ABSTRACT: We report that inactivation of the APC tumor suppressor results in dramatic activation of the NOTUM carboxylesterase, which has potent tumor suppressive activity in APC-null adenomatous epithelium. During progression to adenocarcinoma, APC and TP53 mutations (usually coincident in advanced CRC) synergize, converting NOTUM to an obligate oncoprotein. We provide evidence that the Jekyll-and-Hyde behavior of NOTUM results from its differential activity upon enzymatic targets Glypicans 1 and 4 in early vs. late-stage disease, respectively. Ultimately, we demonstrate that small molecule inhibition of NOTUM activity in a mouse model of metastatic colon cancer is sufficient to arrest primary tumor growth and metastatic colonization. Thus, the extracellular carboxylesterase NOTUM represents a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE198757 | GEO | 2022/12/31

REPOSITORIES: GEO

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APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [scRNA-seq]

Project description:We thought the immediate effects of APC inactivation may represent unexplored therapeutic vulnerabilities in later stages of advanced colorectal adenocarcinoma. We performed transcriptome profiling of epithelial colon organoids immediately after APC inactivation and cross-referenced gene expression changes to the transcriptomes of several mouse models of colon cancer, including colon tumors in an inflammation-induced CRC model (AOM-DSS), a model of familial adenomatous polyposis (FAP, the Apcmin mouse), and an implantation-based model of metastatic adenocarcinoma using Apc/Trp53/KrasG12D/Smad4 quadruple-mutant tumor organoids15 (APKS tumoroids). Of the roughly 150 genes whose expression is acutely induced upon APC loss and remains elevated in these colon cancer models.

2022-12-31 | GSE198758 | GEO

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer.

Project description:APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer.

| PRJNA816830 | ENA

Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit

Project description:Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human disease such as colorectal cancer and Alzheimer’s disease supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we describe the discovery and profile of 8I (ARUK3001185) as a potent, selective and brain pentrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identifed a pair of outstanding hits. Fragment development of these delivered 8I that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in proteomic and pharmacology screens showed 8I to be selective against serine hydrolases, kinases and drug targets.

2022-06-09 | PXD031338 | Pride

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [scRNA-seq]

Project description:APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [scRNA-seq]

| PRJNA816831 | ENA

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [bulk RNA-seq]

Project description:APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [bulk RNA-seq]

| PRJNA816832 | ENA

Gene expression analysis of HepG2 cells by NOTUM RNAi

Project description:We identified human NOTUM, a new member of beta-catenin target gene. The aim of this analysis is to examine downstream genes of NOTUM. Keywords: Gene expression analysis in response to RNA interference HepG2 cells with RNAi duplexed were used. One control (control-low GC) and 2 RNAi duplexes (NOTUM RNAi#1 and #2) for NOTUM silencing were added to HepG2 cells, and total RNAs were isolated at 72 hours after transfection.

2011-03-15 | E-GEOD-6368 | biostudies-arrayexpress

NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [Notum knockdown]

Project description:WNT activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human trophoblast stem (TS) cells, activation of canonical WNT signaling is a key to maintenance of the TS cell stem state. NOTUM, a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for human TS cell differentiation to EVT cells. Canonical WNT signaling is essential for maintaining human trophoblast cell stemness and prevention of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for EVT cell differentiation.

2024-03-06 | GSE206035 | GEO

Notum Regulates the Cusp and Root Patterns in Mouse Molar

Project description:Notumis a direct target of Wnt/β-catenin signaling and plays a crucial role as a Wnt inhibitor within a negative feedback loop. In the tooth, Notum is known to be expressed in odontoblasts, and severe dentin defects and irregular tooth roots have been reported in Notum-deficient mice. However, the precise expression pattern of Notum in early tooth development, and the role of Notum in crown and root patterns remain elusive. In the present study, we identified a novel Notum expression in primary enamel knot (EK), secondary EKs, and dental papilla during tooth development. Notum-deficient mice exhibited enlarged secondary EKs, resulting in broader cusp tips, altered cusp patterns, and reduced concavity in crown outline. These alterations in crown outline led to a reduction in cervical tongue length, thereby inducing root fusion in Notum-deficient mice. Overall, these results suggest that the size of secondary EK size, regulated by the Wnt/Notum negative feedback loop, has a significant impact on the patterns of crown and root during tooth morphogenesis.

2024-06-10 | GSE255946 | GEO

Gene expression analysis of HepG2 cells by NOTUM RNAi

2011-03-15 | GSE6368 | GEO

Transcriptome perturbation analysis from 16 hours APF Drosophila notum.

Project description:Genome-wide transcriptome analysis of genetic pertubations induced in Drosophila notum by the over-expression of the transcription factors Achaete, Asense, E(spl)m3-HLH and Senseless. Transient over-expression of GFP (control), Achaete (Ac), Senseless (Sens), Asense (Ase) and E(spl)m3-HLH transcription factors in Drosophila notum using sca-Gal4, tub-Gal80ts. Transcription factorshave been over-expressed alone or in combinations. Three biological replicates were performed for each conditions.

2014-01-01 | E-GEOD-53010 | biostudies-arrayexpress

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