Merlin rescue drives Wnt signalling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA930687 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23318235.fastq.gz | Fastqsanger.gz | |||
| SRR23318236.fastq.gz | Fastqsanger.gz | |||
| SRR23318237.fastq.gz | Fastqsanger.gz | |||
| SRR23318238_1.fastq.gz | Fastqsanger.gz | |||
| SRR23318238_2.fastq.gz | Fastqsanger.gz |
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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
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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)
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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.
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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.
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