Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

WNT ligands control initiation and progression of human papilloma-virus-driven squamous cell carcinoma

ABSTRACT: Human papilloma virus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT-signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT-ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/b-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT-secretion may thus represent a promising approach for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE108454 | GEO | 2018/12/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Blockade of Wnt secretion by LGK974 after ischemia reperfusion injury

Project description:The LAD of C57BL6 mice were temporally occluded to induce ischemia-reperfusion injury of the heart. Mice received a daily dose of the porcupine inhibitor LGK974 starting directly after the surgery to prevent Wnt protein secretion. Control animals received a DMSO vehicle control. Hearts were extracted 48h after induction of ischemia-reperfusion injury. The infarcted area was identified and processed for RNAseq analysis.

2022-11-02 | GSE185444 | GEO

Metabolomics analysis of AsPC-1 PDAC cells treated with Porcupine inhibitor (LGK974)

Project description:WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) have growth dependency on autocrine WNT ligand signaling, which renders them susceptible to porcupine inhibitors (PORCNi) that block WNT ligand acylation and secretion. For this study, non-targeted metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the PORCNi LGK974. AsPC-1 (RNF43-mutant) PDAC cells were treated with 25 nM LGK974 to explore stable isotope-resolved metabolomics with uniform 1, D-glucose [U13-C6] labeling.

2021-07-19 | ST001902 | MetabolomicsWorkbench

RNA-Seq identification of LGK974 early and late gene targets in AsPC-1

Project description:RNA sequencing with differential gene expression analysis was performed on AsPC-1 pancreatic ductal adenocarcinoma (PDAC) cells at multiple time points with a Porcupine inhibitor (LGK974) to identify mechanisms underpinning transcriptional effects.

2022-04-19 | GSE180615 | GEO

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

Project description: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.

2017-07-01 | GSE98257 | GEO

Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma

Project description:Colon cancer is initiated by stem cells that escape the strict control. In most colon tumors this process is driven through aberrant activation of Wnt signaling by mutations that occur in components acting downstream of the receptor complex and that unfetter tumor cells from the need for Wnt ligands. Here we describe a special type of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells auto-secrete Wnt ligands to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt- dependent colon cancer, that might be responsive to Wnt secretion inhibitors.

2021-09-01 | GSE181738 | GEO

Single cell transcriptomics reveals dysregulated immnue homeostasis in different stages in HPV-induced cutaneous squamous cell carcinoma

Project description:Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer in humans. HPV persistence in the epidermis and excessive wart or squamous is associated with cancer development. Various viral warts can be found on the skin infected with HPV, like condyloma acuminatum and bowenoid papulosis (BP). At present, it is believed that BP is a potential malignant squamous cell carcinoma in situ. In this study, we reported a very rare case of HPV-positive patient with concurrence of BP and cSCC. This patient progressed at a very fast rate and transferred to death quickly. To reveal the cell microenvironment changes from normal skin (NS) to BP and cSCC after HPV infection, we performed scRNA-seq on four pathological lesions skin (NS, BP, paracancerous squamous cell carcinoma (pc-cSCC) and cSCC) from this patient. Among immune cells, CD52+ macrophages were only detected in pc-cSCC and cSCC tissue, and two clusters of T cells, CD8+ Tex cells and CD4+ Tregs as well as matrix cells like MMP1+, MMP11+ fibroblasts were increased in pc-cSCC and cSCC tissue. Widely interactions were also found among specific T cells/macrophages and keratinocytes, which might be involve in the cSCC progress. Targeting these cells or their interactions may be beneficial for the diagnosis and treatment of cSCC.

2024-04-05 | GSE262947 | GEO

Analysis of Porcupine ablation within the uterine epithelium on gene expression within the uterus

Project description:The secretion of mammalian Wnt Ligands within the cell is dependent on the activity of Porcupine, a gene located on the X chromosome that encodes for a membrane bound o-acyl transferase. Porcupine-dependent Wnt signalling was previously shown to be essential for the post-natal maintenance of endometrial glands, structures that are essential for implantation and fertility. Previous data has implicated the multiple members of the Wnt family expressed in the female uterus to be involved in a coordinated crosstalk between the luminal and stromal compartments of the uterus, ensuring the proper development of the uterus and successful fertility. We have generated a conditional mutant of Porcupine in the luminal epithelium (cKOepi) of the uterus, thus eliminating Wnt7a/b and Wnt11, to address the nature of this crosstalk. Unlike global luminal-stromal mutants, post-natal ablation of Porcupine in the luminal epithelium alone does not affect the maintenance of the endometrial glands in adults. Uterine glands are still visible in the adult cKOepi, albeit in a smaller number than that of control uteri. Despite having uterine glands, cKOepi females remain completely infertile. We have attributed the sterility of these females to be in part due to defects in implantation and decidualization; cKOepi fail to respond to decidual induction by artificial means. Interestingly, progesterone supplementation rescues the observed implantation defects, although observed decidual soon seem to become resorptive. Microarray analysis of cKOepi during implantation has reveals several potential targets for luminal WNT that may be responsible for the observed phenotype including: Lef1, Hoxa10, Wnt4, Wnt16 Notch1, Notch4 and Dll4 .

2017-03-21 | GSE96801 | GEO

Global Wnt Inhibition with the Porcupine Inhibitor, LGK974, Decreases Trabecular Bone in a Murine Model with Fibrotic Bone

Project description:G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by an activating mutation in GNAS. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD, for which there are no effective medical treatments.The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remains largely unknown. Single cell RNA sequencing on long-bone stromal cells of 9-week-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or down-regulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.

2023-10-16 | GSE245140 | GEO

Blockade of Wnt secretion by LGK974 after ischemia reperfusion injury

Project description:Blockade of Wnt secretion by LGK974 after ischemia reperfusion injury

| PRJNA769105 | ENA

RNA-seq analysis of mouse (C57/B6) small intestinal tissue after Porcupine Inhibitor treatment or vehicle control.

Project description:Mice were treated with 5 mg/kg LGK974 (Porcupine Inhibitor) for 4.5 days (BID, p.o.). Whole tissue (about 1cm length) from the proximal small intestine was harvested and used for RNA purification. The RNA Integrity was analysed with a NanoChip (Agilent RNA 6000). A total of 2ug of RNA per sample was purified via Poly-A selection and sequenced. Libraries were prepared according to the Illumina TruSeq protocol and sequenced on an Illumina GAIIx. Data was aligned to Mus_musculus.GRCm38.75 library.

2018-01-31 | E-MTAB-4178 | 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