Targeting Dual-specificity Phosphatase 23 to Overcome Chemoresistance and Stem Cell-like Behavior in Non-small Cell Lung Cancer Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE288032 | GEO | 2025/01/31
REPOSITORIES: GEO
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Project description:Microenvironment has been suggested as an important factor contributing to how the colorectal cancer cells escape therapy, but the exact mechanism leading to chemoresistance remains elusive. Here, through modeling in vitro by cocultivation of patient-derived cancer associated fibroblasts (CAFs) with cancer stem cells (CSCs), we show that CAFs-secreted TGF-β2 is a key stromal factor that coordinates with hypoxia to promote CSC stemness and resistance to chemotherapy. GLI2, a key transcription factor of Hedgehog pathway, was identified as both necessary and sufficient in this process in which TGF-β and hypoxia-inducible factor (HIF-1α) synergize to directly induce GLI2 expression. Conversely, CSC-secreted TGF-β is also important to support the growth of CAFs but instead induce death of normal fibroblasts, suggesting a reciprocal mechanism to selectively support the CAF-CSC interaction. Small molecule inhibition of both TGF-β and GLI2 effectively reversed the chemoresistance. Finally, expression of TGFB2/HIF1A/GLI2 gene signature as a functional readout of this resistance pathway defines worse clinical outcomes and predicts patients relapse. Our observations uncover a key role of TGF-β/HIF-1α/GLI2 in microenvironment-mediated chemoresistance and reveal novel biomarker and targeting strategies to identify and treat the high risk CRC patients.
2019-01-30 | GSE93254 | GEO
Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile Sox2-GFP expressing CSC to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Two different biological replicates from SOX2-GFP+ and SOX2-GFP- TECs (control) from 2 different SCC from 2 different mice were analysed. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.
2014-06-08 | E-GEOD-55737 | biostudies-arrayexpress
Project description:Epidermal growth factor receptor (EGFR) inhibitors, as targeted therapies for non-small-cell lung cancer (NSCLC), have significantly enhanced patient survival and quality of life. However, despite these advancements, a significant proportion of patients exhibit resistance to EGFR inhibitors, limiting their overall treatment effectiveness. This study investigates the synergistic effects of combining Paeoniae Radix (PR) with the EGFR inhibitors erlotinib and gefitinib to overcome this resistance. The transcriptomic analysis of PR treatment revealed its potential to reverse the gene signature associated with resistance to EGFR inhibitors, as identified through analysis of a cell line database in EGFR mutant NSCLC. Combination treatment experiments validated that PR increased responsiveness to erlotinib and gefitinib in H1650 and H1975 NSCLC cells. By combining molecular experiments and transcriptome analysis, we found that PR may suppress resistance by modulating the Aurora B and apoptosis pathways. Notably, the combination therapy upregulated the apoptosis pathway and downregulated the Aurora B pathway more than single drug treatments. These results may contribute to the development of natural product-based combination therapeutic strategies to inhibit drug resistance in NSCLC.
2024-03-24 | GSE261880 | GEO
Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile Sox2-GFP expressing CSC to uncover a gene network regulated by Sox2 in primary tumour cells in vivo.
2014-06-08 | GSE55737 | GEO
Project description:BACKGROUND: Therapy resistance remains one of the major challenges to improve the prognosis of patients with pancreatic cancer. Chemoresistant cells, which potentially also display cancer stem cell (CSC) characteristics, can be isolated using the side population (SP) technique. Our aim was to search for a SP in human pancreatic ductal adenocarcinoma (PDAC) and to examine its chemoresistance and CSC phenotype. RESULTS: A SP was identified in all PDAC samples, expanded and analyzed as first-generation xenografts. This SP was more resistant to gemcitabine than the other tumour cells as analyzed in vivo. Whole-genome expression profiling of the SP revealed upregulation of genes related to therapy resistance, apoptotic regulation and epithelial-mesenchymal transition. In addition, the SP displayed higher tumourigenic (CSC) activity than the other main tumour cell population (MP) as analyzed in vitro by sphere-forming capacity. CONCLUSION: We identified a SP in human PDAC and uncovered a chemoresistant and CSC-associated phenotype. This SP may represent a new therapeutic target in pancreatic cancer. Micro-array analysis was performed on SP and MP samples of 5 xenografts, grown from 5 different human PDAC samples.
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Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile tumour epithelial cells upon Sox2 deletion to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Microarray analysis was performed on FACS isolated Epcam+ a6+ TECs from 3 different biological experiments following TAM administration to K14CREER:SOX2fl/fl and control mice. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.
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2021-05-25 | PXD025902 | Pride
Project description:Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyper-aggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. GBM specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide new evidence that diet modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
2021-05-25 | PXD023685 | Pride
Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy, while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks including 4,444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1 regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance making its inhibition a promising target for future combination therapy.
2023-12-01 | GSE248856 | GEO
Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy, while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks including 4,444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1 regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance making its inhibition a promising target for future combination therapy.
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