Merlin rescue drives Wnt signalling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA930687 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To investigate the effect of Merlin rescue on cell proliferation in 3D, we grew subcutaneous xenografts from NF2-deficient CH-157MN meningioma cells harboring doxycycline inducible WT-Merlin. Mice were treated with or without doxycycline and Merlin induction was confirmed 24 hours after induction with Western blot. We performed single-cell RNA sequencing on five Merlin-deficient tumors and seven Merlin rescue tumors
2023-08-07 | GSE224347 | GEO
Project description:Hypothesis and proof of concept:
Our hypothesis is that increase in cellular iron import proteins (TfR1, DMT1) occur early in the adenoma-carcinoma sequence through mutations in APC and lead to cellular iron loading. As demonstrated in our previous work the effects of this iron loading is to mediate increased Wnt signalling resulting in c-myc induction. This in turn serves to increase the expression of iron import proteins (TfR1, DMT1) and decrease the expression of iron export (ferroportin [FPN]) and storage (ferritin) proteins. Such a hypothesis explains how Wnt signalling controls iron metabolism and ensures that there is adequate cellular iron for ATP generation and cellular proliferation.
Experimental design:
To test such a hypothesis we aim to prospectively collect the following colorectal tissue from patients attending for colonoscopy:
1. Normal colonic mucosa in patients with no colorectal pathology (n = 30)
2. Polyps and matched normal colon (n = 30)
3. Colorectal cancers and matched normal colon (n = 30)
We also intend to collect serum and urine from the following patient groups:
4. Normal colonoscopy (n = 30)
5. Colorectal adenomas (n = 30)
6. Colorectal cancers (n = 30)
Primary outcome(s): Measured at baseline, using the expression of proteins in the tissue and serum to detect the cellular and systemic iron transport proteins. The techniques used will include mass spectrometry, western blotting, real time PCR and immunohistochemistry.
| 2416626 | ecrin-mdr-crc
Project description:Meningiomas are the most common primary intracranial tumors and are associated with inactivation of the tumor suppressor NF2/Merlin, but one-third of meningiomas retain Merlin expression and typically have favorable clinical outcomes. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that predict meningioma outcomes and could be used to guide treatment de-escalation or imaging surveillance of Merlin-intact meningiomas are lacking. Here we integrate single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma cells, xenografts, and human patients to define biochemical mechanisms and an imaging biomarker that distinguish Merlin-intact meningiomas with favorable clinical outcomes from meningiomas with unfavorable clinical outcomes. We find Merlin drives meningioma Wnt signaling and tumor growth through a feed-forward mechanism that requires Merlin dephosphorylation on serine 13 (S13) to attenuate inhibitory interactions with β-catenin and activate the Wnt pathway. Meningioma MRI analyses of xenografts and human patients show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC) on diffusionweighted imaging. In sum, our results shed light on Merlin posttranslational modifications that regulate meningioma Wnt signaling and tumor growth in tumors without NF2/Merlin inactivation. To translate these findings to clinical practice, we establish a non-invasive imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with favorable meningiomas.
2024-07-04 | PXD053578 | Pride
Project description:The impact of WNT signalling activity on the acquisition and restriction of lineage propensity of germ layer progenitors and the gene network activity for cell fate decision during the development of the embryonic head was modelled in the epiblast stem cells derived and maintained under different signalling conditions. Our findings showed that the modulation of WNT activity is critical for the specification of the anterior (head) tissue progenitors in the multipotent early epiblast and the repression of WNT activity enhances the ectoderm lineage potency of the epiblast cells and poises the activation of endogenous WNT activity that drives neurogenesis during head morphogenesis.
2019-03-31 | GSE117756 | GEO
Project description:Centrosomes control cell motility, polarity and migration that are thought to be mediated by their microtubule-organizing capacity. In this study we demonstrate that WNT signalling drives a distinct form of non-directional cell motility that requires a key centrosome module, but not microtubules or centrosomes. Upon exosome mobilization of Planar Cell Polarity proteins, we show that DVL2 orchestrates recruitment of a CEP192-PLK4/AURKB complex to the cell cortex where PLK4/AURKB act redundantly to drive protrusive activity and cell motility. This is mediated by coordination of formin-dependent actin remodelling through displacement of cortically localized DAAM1 for DAAM2. Furthermore, abnormal expression of PLK4, AURKB and DAAM1 is associated with poor outcomes in breast and bladder cancers. Thus, a centrosomal module plays an atypical function in WNT signalling and actin nucleation that is critical for cancer cell motility and is associated with more aggressive cancers. These studies have broad implications in how contextual signalling controls distinct modes of cell migration.
2019-04-26 | GSE129871 | GEO
Project description:WNT signalling activity on epiblast cells
| PRJNA401007 | ENA
Project description:The Wnt/ß-catenin pathway is orchestrating the development of the blood-brain barrier (BBB), but its downstream mediators have remained elusive. To identify potential effectors, we generated an endothelial cell specific Axin1 over-expressing mouse model, AOEiEC. We found that in AOEiE mice Wnt/ß-catenin signalling was down regulated leading to premature regression and remodelling without directly compromising BBB integrity. Interestingly, by comparing transcriptomes of endothelial cells from control and AOEiEC mice, we identified Adamtsl2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the cerebral vasculature during development. Importantly, loss-of-function and gain-of-function experiments revealed that Adamtsl2 alone was sufficient to rescue CNS vascular defects seen upon Wnt-signalling inhibition. Furthermore, using various cell and animal models we demonstrate that Adamtsl2 exerts its function by fine-tuning the TGFβ signalling pathway in CNS vessels. In conclusion, this study implicates Adamtsl2 as a mediator of Wnt/ß-catenin signalling during BBB development by linking it to TGFβ signalling.
2019-01-31 | GSE77874 | GEO
Project description:The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here we show that injection of Fam83f mRNA into Xenopus embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whilst ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it. We demonstrate that FAM83F is farnesylated and interacts and co-localises with CK1α at the plasma membrane. This interaction with CK1α is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1α fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3β, because the attenuation of Wnt signalling caused by loss of FAM83F can be rescued by GSK-3 inhibition. Introduction of a farnesyl-deficient mutant of FAM83F in cells through CRISPR/Cas9 genome editing redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.
2020-12-23 | PXD023121 | Pride
Project description:Atypical function of a centrosomal module in WNT signalling drives contextual cancer cell motility
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Project description:Ciliary associated extracellular vesicles modulate WNT signalling
| PRJNA641812 | ENA