Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1085291 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR28261300_1.fastq.gz | Fastqsanger.gz | |||
| SRR28261300_2.fastq.gz | Fastqsanger.gz | |||
| SRR28261301_1.fastq.gz | Fastqsanger.gz | |||
| SRR28261301_2.fastq.gz | Fastqsanger.gz |
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Project description:<p>The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.</p>
2021-10-15 | MTBLS1925 | MetaboLights
Project description:SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies novel non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
2022-12-13 | PXD038726 | Pride
Project description:The incidence for pancreatic ductal adenocarcinoma (PDAC) is rising which has a low survival rate. In cancer, Epithelial-to-Mesenchymal transition (EMT) contribute to an aggressive phenotype. Protein Phosphatase Type 2A (PP2A) are initially regarded as tumor suppressors, the connection with EMT in patients is uncertain. We investigated the relation of a ‘PP2A’ gene signature (en-compassing catalytic, structural and regulatory subunits; and endogenous PP2A inhibitors and activators) with EMT in PDAC patients. We could demonstrate a link between PDAC and EMT in four patient datasets using datamining, correlation study and gene set analysis. Furthermore, we identified a strong association of PP2A with EMT in advanced pancreatic cancer patients and in particular a significant upregulation of PP2A inhibitor genes in aggressive/EMT-high PDAC. In vitro, pharmacological inhibition of PP2A through Okadaic acid induced EMT in human pancreatic cells. Two different cell models were developed and their morphology, gene and protein expression determined. In the more advanced OA-induced EMT model (OA7G), statistical changes in proteins of natural PP2A-inhibitors was observed and this requires further investigations. Translationally, these observations indicate that PP2A could be a central factor in cancer and it is therefore attractive to test compounds that can target PP2A enzyme activity in PDAC.
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Project description:The receptor tyrosine kinase AXL promotes tumor progression, metastasis and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we report that activation of AXL results in TANK-binding kinase 1 (TBK1) phosphorylation, subsequent TBK1-dependent phosphorylation of AKT3 (pAKT3) and nuclear accumulation of pAKT3 and the EMT transcription factor (EMT-TF) Snail. Mechanistically, we show that (i) TBK1 directly binds and phosphorylates AKT3, in an mTORC1 dependent manner. Once activated, AKT3 interacts with Snail and promotes the accumulation of nuclear Snail to drive EMT. Congruently, in human pancreatic ductaladenocarcinoma tissue, nuclear AKT3 co-localizes with Snail and correlates with worse clinical outcome. AKT3 knockout in tumor cells significantly reduced metastatic spread in mice suggesting that selective AKT3 inhibition represents a novel therapeutic avenue for targeting EMT in aggressive cancers.
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Project description:Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant lung cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.
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Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia. Transcriptomes of KCiMist1G; p120wt/wt and KCiMist1G; p120f/f pancreases were compared, with three replicates each, using microarray.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial mesenchymal transdifferentiation (EMT) in adaption to environmental cues, including inflammation, a process that combines tumour cell dedifferentiation with dissemination and acquisition of stemness features. However, the mechanisms coupling inflammation-induced signalling pathways with EMT and stemness remain largely unknown. Here, we reveal the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity.
2015-02-10 | E-MTAB-2324 | biostudies-arrayexpress
Project description:K-Ras mutations occur frequently in epithelial cancers. Using shRNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-Ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets.
2009-03-06 | GSE15126 | GEO
Project description:Epithelial-mesenchymal transition (EMT) is initiated and regulated by a transcriptional reprogramming in response to microenvironmental cues. How cancer cells overcome the lack of such cues during the metastatic journey remains unclear. Here we report a novel positive-feedback loop of EMT that maintains the mesenchymal traits of cancer cells during metastasis. Using subgenome-wide screening, we identified KLHL23 as a tumor invasion suppressor, which binds to actin and suppresses actin-filament formation. Silencing or ectopic expression of KLHL23 induces EMT or MET (mesenchymal-epithelial transition), respectively, through its action on actin dynamics. Increased actin-dynamics by silencing KLHL23 or treatment with F-actin disruptors or inducers enhances the EMT transcriptional reprogramming via the induction of ROS, HIF-1a, HIF-2a and NOTCH signalling pathways in cancer cells under stress or ongoing EMT. Downregulation of KLHL23 is found in human liver and pancreatic cancers and associated with tumor metastasis and poor prognosis.
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2022-03-14 | GSE190095 | GEO