Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

R-Spondin chromosome rearrangements drive Wnt-dependent tumor initiation and maintenance in the intestine

ABSTRACT: Defining the genetic drivers of cancer progression is key to understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumor development in vivo, without additional cooperating genetic events. Rspo fusion tumors are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumor clearance from the intestinal mucosa without effects on normal intestinal crypts. Together, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumor development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE98257 | GEO | 2017/07/01

SECONDARY ACCESSION(S): PRJNA384433

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Gene Expression Profiles of 4 CRC PDX models treated by RSPO3 antagonist.

Project description:RSPO is a WNT pathway activator and functions as a potent regulator of stem cell growth in colon. RSPO family members were produced by several human tumors representing multiple tumor types including ovarian, pancreatic, colon, breast and lung cancer. Specific monoclonal antibody antagonists of RSPO family members were developed. In human patient-derived tumor xenograft models, anti-RSPO treatment markedly inhibited tumor growth either as single agents or in combination with chemotherapy. Furthermore, blockade of RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. In order to assess the impact of RSPO3 inhibition and gain insight in the anti-RSPO3 treatment mechanism of action, the global gene expression profiles of 4 human colorectal cancer patient derived models (PDX) were performed using Affymetrix microarray for the xenografts treated by the anti-RSPO3 antibody.

2016-03-03 | GSE73906 | GEO

Gastric Lgr5+ cells are programmed by Rspo3 to shield the gland from infection

Project description:R-spondin (Rspo) signaling is crucial for stem cell renewal and tissue homeostasis in the gastrointestinal tract. In the stomach, Rspo is secreted from myofibroblasts and controls epithelial gland regeneration by inducing proliferation of Wnt-responsive Axin2+ cells in the isthmus of the gland. Infection with H. pylori results in increased expression of stromal Rspo, leading to an expansion of Axin2+ isthmus stem cells and gland hyperplasia. Lgr5+ cells in the gland base are exposed to Rspo3 but the effects of this are not well understood. Here we demonstrate that apart from its activity as a mitogen, endogenous Rspo3 regulates gene expression of Lgr5+ cells in the gastric gland base. Surprisingly, Rspo3 induces differentiation within the Lgr5+ compartment towards secretory deep mucous cells. Moreover, the Rspo3-Lgr5 axis turns out to be a stimulus of epithelial antimicrobial defense. Infection with H. pylori induces a strong antimicrobial response, with Lgr5+ cells expressing antimicrobial compounds that are secreted into the lumen in an Rspo3-dependent manner. Depletion of Lgr5+ cells or knockout of Rspo3 in myofibroblasts leads to hyper-colonization of gastric glands, including the stem cell compartment, whereas systemic application of recombinant Rspo clears H. pylori from the glands. We provide an intriguing, unexpected feature of the Rspo3-Lgr5 axis in the stomach, exhibiting antimicrobial self-protection of the gland to protect the stem cell compartment from invading pathogens.

2019-03-25 | GSE124930 | GEO

Gastric Lgr5+ stem cells secrete antimicrobial proteins to shield against infection

Project description:R-spondin (Rspo) signaling is crucial for stem cell renewal and tissue homeostasis in the gastrointestinal tract. In the stomach, Rspo is secreted from myofibroblasts and controls epithelial gland regeneration by inducing proliferation of Wnt-responsive Axin2+ cells. Infection with H. pylori results in increased expression of stromal Rspo, leading to an expansion of Axin2+ isthmus stem cells and gland hyperplasia. Lgr5+ stem cells are exposed to Rspo3 but the effects of this are not well understood. Here we demonstrate that in addition to its effect as a mitogen, endogenous Rspo3 regulates the gene expression of Lgr5+ cells in the gland base in both antrum and corpus. Rspo3 inhibits proliferation and induces differentiation within the Lgr5+ compartment towards a secretory phenotype. Strikingly, the Rspo3-Lgr5 axis turns out to be required for epithelial antimicrobial defense. Infection with H. pylori induces a strong antimicrobial response, with Lgr5+ cells expressing antimicrobial compounds that are secreted into the lumen in an Rspo3-dependent manner. Depletion of Lgr5+ cells or knockout of Rspo3 in myofibroblasts leads to dramatic hyper-colonization of gastric glands, including the stem cell compartment, whereas systemic application of recombinant Rspo is sufficient to clear H. pylori from the glands. We provide an intriguing, unexpected feature of Lgr5+ cells, exhibiting an indivisible connection between stem cell signaling and antimicrobial self-protection.

2019-01-01 | GSE108729 | GEO

RNA-Seq of sorted Lgr5+ cells with and without infection with Helicobacter pylori

Project description:Wnt signaling stimulated by R-spondin (Rspo) via binding to Lgr family members is crucial for stem cell renewal and tissue homeostasis in the gastrointestinal tract. In the stomach, Rspo is secreted by myofibroblasts and controls epithelial gland regeneration by inducing proliferation of Wnt-responsive Axin2+ cells in the isthmus of glands. Infection with Helicobacter pylori results in increased expression of stromal Rspo, leading to an expansion of Axin2+ isthmus stem cells and gland hyperplasia. Basal Lgr5+ cells are exposed to Rspo3 but the effects of this are not well understood. Here we demonstrate that, in the antrum, endogenous Rspo3, apart from its activity as a mitogen, regulates Lgr5+ cells in the gland base and induces their differentiation towards secretory cells.

2019-04-02 | GSE129107 | GEO

Gene expression in Rspo2 and/or Wnt3a treated C57MG mouse mammary epithelial cells

Project description:R-spondins (Rspos) comprise a family of four secreted proteins that have important roles in cell proliferation, cell fate determination and organogenesis. Rspos typically exert their effects by potentiating the Wnt/β-catenin signaling pathway. To systematically investigate the impact of Rspo/Wnt on gene expression, we performed a microarray analysis using C57MG mouse mammary epithelial cells treated with recombinant Rspo2 and/or Wnt3a. This study compares gene expression in C57MG cells after 24h treatment with recombinant Rspo2 and recombinant Wnt3a alone or in combination versus BSA treatment. Control cells were treated with BSA, since it was used as carrier for the recombinant proteins. Each treatment was done in biological triplicate.

2011-10-04 | E-GEOD-32096 | biostudies-arrayexpress

Gene expression in Rspo2 and/or Wnt3a treated C57MG mouse mammary epithelial cells

2011-10-05 | GSE32096 | GEO

Novel kinase fusion oncogenes in post-Chernobyl radiation-induced pediatric thyroid cancers

Project description:Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We identified non-overlapping somatic driver mutations in all 26 cases of post-Chernobyl thyroid cancers we studied through candidate gene assays and next generation RNA-sequencing. We found that 22/26 harbored fusion oncogenes arising primarily through intrachromosomal rearrangements. Altogether 23/26 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the two novel somatic rearrangements ETV6-NTRK3 and AGK-BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. A lower prevalence of fusion oncogenes was found in a cohort of pediatric thyroid cancers from children from the same geographical regions that were not exposed to radiation. Radiation-induced thyroid cancers are a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program. Examination of transcriptome profiles and genetic somatic changes in thyroid cancer.

2013-10-25 | E-GEOD-48850 | biostudies-arrayexpress

5' droplet-based single cell RNA sequencing of human colorectal cancer and normal organoids

Project description:Using 5' droplet-based single cell sequencing, we profiled single cells dervied from human colorectal cancer organoids carrying either APC mutation or RSPO fusion, and paired normal colon organoids for the later.

2020-03-31 | GSE142116 | GEO

Genentech Colon Cancer Screen

Project description:Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

| EGAS00001000288 | EGA

SNP array of AML and MDS specimens with dic(20;22)

Project description:This study describes a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is the first description of a recurrent telomere fusion event in myeloid malignancy. The derivative chromosome is further characterised by the presence of nucleolus organiser region material from the chromosome 22 short arm, loss of the putative tumour suppressor gene at 20q12 and secondary rearrangements including gain or amplification of 20q material adjacent to the deletion encompassing 20q12. The presence of residual telomere sequence at the site of translocation in three of the four cases is compelling support for telomere fusion, and supports previous evidence that over half of dicentric chromosomes involving 20q are produced by telomere fusion events. We propose that the sequence of events producing this chromosome abnormality is initial formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, followed by breakage-fusion-bridge cycles causing 20q12 deletion and 20q11.2 gain which provide a growth advantage to the cell. Selection of these clones contributes to leukaemogenesis. Finding recurrent patterns in the complex genome reorganisation events which characterise poor prognosis, complex karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies. The sample consists of leukaemia specimens from three different cases of AML and MDS. The consistent feature was the presence of a dicentric chromosome formed from chromosomes 20 and 22.

2016-06-30 | E-GEOD-64050 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data