Diverse Targets of β-catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE67571 | GEO | 2015/04/04
SECONDARY ACCESSION(S): PRJNA280281
REPOSITORIES: GEO
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Project description:Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that is activated by the epithelial-mesenchymal transition (EMT) program. However, the mechanistic relationship between the EMT and Wnt pathway in CSCs remains unclear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the ?-catenin/E-cadherin/Sox15 complex to the ?-catenin/Twist1/TCF4 complex, which then binds to CSC-related gene promoters. In tandem co-IP and re-ChIP experiments using epithelial-type cells, Sox15 associated with the ?-catenin/E-cadherin complex and then bound to the proximal promoter region of CASP3, consequently resulting in Twist1 cleavage and negatively regulating the ?-catenin–elicited promotion of the CSC phenotype. During the EMT, Twist1 in complex with ?-catenin enhanced ?-catenin/TCF4 transcriptional activity, which includes binding to the proximal promoter region of ABCG2, a marker of CSCs. For clinical application, the five-gene signature nuclear ?-cateninHigh/nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High may be a valuable prognostic marker in patients with human lung cancer. Total cellular RNA was extracted from LM and HM20 cells after treatment with or without Wnt3a for 24hours. Human lung cancer A549 cell–derived spheres were transferred back to adhesive tissue culture plates (LM cells). To establish an EMT/metastasis cell model, LM cells were seeded onto Matrigel-coated Boyden chamber membranes. HM20 cells were serially selected for Matrigel invasion 20 times.
2015-04-04 | E-GEOD-67571 | biostudies-arrayexpress
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248084 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248083 | GEO
Project description:To determine the critical mediator of TRIB3-enhanced Wnt/beta-catenin signaling, we examined the expression profile of genes that might regulate Wnt/beta-catenin by using mRNA microarrays. Aberrant activation of Wnt/beta-catenin signaling pathway is a major reason for the tumorigenesis of Colon cancer. However, no specific drug targeting this pathway has been in the market. Surgery combined with cytotoxic drugs are still the major therapy methods toward colon cancer. These highlighted the need for therapeutics with alternative mechanisms of action. Here we report that the elevated TRIB3 expression associates positively with Wnt/beta-catenin signaling pathway. TRIB3 interacts with beta-catenin and TCF4 to enhance the associations between TCF4/beta-catenin target genes’ promoters, which upregulates the transcriptional activity of beta-catenin, thus to promote the CSC stemness and colon cancer tumorigenesis.
2020-11-17 | GSE107094 | GEO
Project description:Cancer stem cells (CSCs) play a key role in tumour growth and metastasis. Although an expansion of CSC population was previously described in advanced cutaneous squamous cell carcinoma (SCC), it remains unknown whether CSC regulatory mechanisms also change through tumour progression to promote malignancy. Here, we generate mouse models of skin SCCs to study alterations in CSC regulation over progression. We found that features of CSCs change at late stage of progression, correlating with a switch from epithelial to mesenchymal tumour shape. beta-catenin and EGFR signalling are down-regulated, whereas autocrine FGFR1 and PDGFR alpha pathways are up-regulated in CSCs of advanced tumours. Inhibition of FGFR and PDGFR signalling repress malignant SCCs growth and metastasis, respectively. An enhanced epithelial-to-mesenchymal transition (EMT) program and over-expression of PDGFR alpha and FGFR1 are observed in malignant human skin SCCs, suggesting that these pathways are also induced over human SCC progression. Therefore, uncover signalling pathways controlling CSCs at specific stage of progression may improve the selection of more accurate targeted therapeutic strategies according to tumour stage, blocking SCC relapse and metastasis.
2016-01-08 | GSE59439 | GEO
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. In vivo liver samples in 4 conditions: Betacat activated (WCE, Tcf4 chipseq, Betacat chipseq, mRNAseq with 2 replicates), Betacat null (WCE, Tcf4 chipseq, mRNAseq with 2 replicates), Betacat control (mRNAseq with 2 replicates), Wild type (mRNAseq with 2 replicates)
2014-01-18 | E-GEOD-35213 | biostudies-arrayexpress
Project description:Increasing evidence suggests that cancer arises from cells that are capable of initiating and sustaining neoplastic tissue growth, termed cancer stem cells (CSCs). Of central scientific and clinical relevance, cells with CSC properties are enriched for chemo- and radiation resistance and therefore may represent a population of cells that must be therapeutically targeted to prevent cancer recurrence/relapse 1. Human CSCs were first isolated in neoplastic hematopoietic tissue that manifests leukemias such as adult acute myeloid leukemia (AML) 2. AML stem cells represent a benchmark model of human CSC biology, ultimately motivating foundational studies leading to the identification of CSCs from solid tumours such as breast and colon 3. Independent of tissue type, a consistent feature of CSCs is their uncontrolled self-renewal capacity and differentiation blockade that have been commonly related to aberrant activation of pro-oncogenic events such as dysregulation of CBP/p300 transcriptional regulation involving β-catenin 4. However, the transcriptional networks involving CBP/p300/β-catenin complex have been shown to be equally critical to maintain normal stem cell (SCs) self-renewal for tissue homeostasis and regeneration 5. Here, we identify Sam68 as a distinct target that affords the ability to uniquely regulate CBP mediated transcription in human CSCs. Using a small molecule that targets Sam68, we reveal that shifting its affinity for CBP disrupts CBP/β-catenin complexes, leading to immediate changes in histone H3 (K14 and K18) acetylation. Chemical targeting of Sam68 induced global changes in transcriptional programs of patient AML cells involving apoptosis and differentiation and was able to uniquely reduce neoplastic self-renewal of human CSCs in an in vivo model of patient specific acute myeloid leukemia (AML). Our study establishes an approach whereby the CBP/β-catenin transcriptome can be uniquely targeted via Sam68 based vulnerability of CSCs that impacts neoplastic differentiation and self-renewal.
2017-10-10 | GSE34965 | GEO
Project description:Cancer stem cells (CSCs) play a key role in tumour growth and metastasis. Although an expansion of CSC population was previously described in advanced cutaneous squamous cell carcinoma (SCC), it remains unknown whether CSC regulatory mechanisms also change through tumour progression to promote malignancy. Here, we generate mouse models of skin SCCs to study alterations in CSC regulation over progression. We found that features of CSCs change at late stage of progression, correlating with a switch from epithelial to mesenchymal tumour shape. beta-catenin and EGFR signalling are down-regulated, whereas autocrine FGFR1 and PDGFR alpha pathways are up-regulated in CSCs of advanced tumours. Inhibition of FGFR and PDGFR signalling repress malignant SCCs growth and metastasis, respectively. An enhanced epithelial-to-mesenchymal transition (EMT) program and over-expression of PDGFR alpha and FGFR1 are observed in malignant human skin SCCs, suggesting that these pathways are also induced over human SCC progression. Therefore, uncover signalling pathways controlling CSCs at specific stage of progression may improve the selection of more accurate targeted therapeutic strategies according to tumour stage, blocking SCC relapse and metastasis. Mouse models of skin SCCs progression were first generated. For that, individual samples of spontaneous or DMBA-TPA induced skin SCCs generated in K14-HPV16 mice were orthotopically engrafted in immunodeficient mice and then serially transplanted, generating lineages in which the progression from WD-SCCs to PD-SCCs was observed. Then, tumour cells expressing CD34 and alpha 6-integrin, previously identified as cutaneous cancer stem cells, were isolated by flow cytometry-sorter from WD-SCCs and PD-SCCs of different tumour lineages. RNA extraction and hybridization on Affymetrix microarrays was carried out to compare whole gene profiling of these populations of CSCs.
2016-01-08 | E-GEOD-59439 | biostudies-arrayexpress
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation.
2014-01-18 | GSE35213 | GEO
Project description:Secreted frizzled-related proteins (SFRPs) are mainly known for their role as extracellular modulators and tumor suppressors that down-regulate Wnt signaling. Using the established (CRISPR/Cas9 targeting promoters of SFRPs and targeting SFRPs transcript) system, we find that nuclear SFRPs interact with β-catenin and either promote or suppress TCF4 recruitment. SFRPs bind with β-catenin on both their N and C termini, which the repressive effects caused by SFRP-β-catenin-N-terminus binding overpower the promoting effects of their binding at the C terminus. By high Wnt activity, β-catenin and SFRPs only bind with their C termini, which results in the up-regulation of β-catenin transcriptional activity and cancer stem cell (CSC)-related genes. Furthermore, we identify disulfide bonds of the CRD domain and two threonine phosphorylation events of the NTR domain of SFRPs that are essential for their role as biphasic modulators, suggesting that SFRPs are biphasic modulators of Wnt signaling-elicited CSC properties beyond extracellular control.
2019-07-09 | GSE133943 | GEO