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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

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Blockade of Wnt secretion by LGK974 after ischemia reperfusion injury

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2021-07-19 | ST001902 | MetabolomicsWorkbench

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.

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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

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

Genes expression of cervical squamous cell carcinoma, CaSki cells, treated with or without recombinant TGF-b1 (2 ng/mL)

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