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Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells

ABSTRACT: Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells

PROVIDER: PRJNA464036 | ENA |

REPOSITORIES: ENA

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Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Affymetrix]

Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.

2018-05-08 | GSE114060 | GEO

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Illumina]

2018-05-08 | GSE114059 | GEO

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Affymetrix]

Project description:Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Affymetrix]

| PRJNA464039 | ENA

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Illumina]

Project description:Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Illumina]

| PRJNA464038 | ENA

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-05-08 | GSE114061 | GEO

Tpl-2 and MEK small molecule inhibitors

Project description:Tpl-2 and MEK small molecule inhibitors

| PRJNA328166 | ENA

TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

Project description:TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

| PRJEB61535 | ENA

TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

Project description:TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

| PRJEB55174 | ENA

A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling

Project description:Objective Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. Design We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. Results Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. Conclusions These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

2015-10-05 | GSE48643 | GEO

Wnt signalling in colon cancer

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

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