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Wnt addiction of genetically defined cancers reversed by PORCN inhibition

ABSTRACT: Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. Inhibition of PORCN in RSPO3-translocated cancers via treatment with ETC-159 causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69687 | GEO | 2015/08/12

SECONDARY ACCESSION(S): PRJNA286198

REPOSITORIES: GEO

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Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Project description:Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. Inhibition of PORCN in RSPO3-translocated cancers via treatment with ETC-159 causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers. RNA-seq of colorectal PDXs with confirmed R-spondin fusion genes. RNA-seq was performed in 2 conditions (Vehicle and treatment with ETC-159 (an inhibitor of PORCN) with 4 replicates per condition.

2015-08-12 | E-GEOD-69687 | biostudies-arrayexpress

Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

Project description:Wnt/b-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (PorcnDel/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of PorcnDel organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable, and that stromal production of Wnts can fully support normal murine intestinal homeostasis. Microarray was performed on samples enriched for stromal or epithelial cells from small intestine from Porcn(Del)/Villin-Cre and Porcn(WT)/Villin-Cre male C57Bl/6 mice.

2014-04-19 | E-GEOD-56911 | biostudies-arrayexpress

Transcriptional response to PORCN inhibition using an in vivo model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II) in EP300 knockout and WT cells

Project description:RNF43-mutant pancreatic tumors are driven by Wnt signaling and sensitive to Wnt inhibition, e.g. PORCN inhibitors. However, some RNF43-mutant pancreatic cancers are intrinsically resistant to Wnt inhibition. We identified that EP300 mutations confer resistance to PORCN inhibitors in RNF43-mutant pancreatic cancers. We found that EP300 knockout down-regulated GATA6 expression and GATA6-regulated differentiation program, making the anti-differentiation roles of Wnt signaling dispensable.

2022-06-16 | GSE183893 | GEO

Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

2014-04-19 | GSE56911 | GEO

Transcriptional response to PORCN inhibition using an orthotopic model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II)

Project description:Timecourse RNA-seq of response to PORCN inhibition, using ETC-159, in an orthotopic model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II).

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Transcriptional response to PORCN inhibition using an in vitro model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II)

Project description:SRP136961 - PRJNA448457 - RNA-seq of response to PORCN inhibition, using ETC-159, in vitro of RNF43 mutant pancreatic adenocarcinoma (HPAF-II).

2018-12-04 | GSE118190 | GEO

Transcriptional response to PORCN inhibition using a subcutaneous model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II)

Project description:SRP136970 - PRJNA448481 - RNA-seq of response to PORCN inhibition, using ETC-159,in a subcutanenous model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II).

2018-12-04 | GSE118179 | GEO

Homo sapiens

Project description:Wnt addiction of genetically defined cancers reversed by PORCN inhibition

| PRJNA286198 | ENA

Transcriptional response to PORCN inhibition using an HPAF-II orthotopic model upon MYC perturbation

Project description:SRP137043 - PRJNA448654 - Timecourse RNA-seq response to PORCN inhibition using an HPAF-II orthotopic model with different MYC states

2018-12-04 | GSE118231 | GEO

Identification of endothelial genes co-regulated upon endothelial Evi/Wls and Rspo3 deletion

Project description:Inducible endothelial Rspo3 deletion resulted in perturbed developmental and tumor vascular remodeling. Rspo3-iECKO mice strikingly phenocopied the non-canonical WNT signaling-induced vascular defects of mice deleted for the WNT secretion factor Evi/Wls. An endothelial screen for RSPO3 and EVI/WLS co-regulated genes identified novel target genes, which could be linked to WNT/Ca2+/NFAT signaling. In summary, the study identifies endothelial RSPO3-driven non canonical WNT/Ca2+/NFAT signaling as critical maintenance pathway of the remodeling vasculature.

2016-02-03 | GSE75836 | GEO

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