Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance [Hi-C]
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ABSTRACT:
PROVIDER: PRJNA695073 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13537349_1.fastq.gz | Fastqsanger.gz | |||
| SRR13537349_2.fastq.gz | Fastqsanger.gz | |||
| SRR13537350_1.fastq.gz | Fastqsanger.gz | |||
| SRR13537350_2.fastq.gz | Fastqsanger.gz | |||
| SRR13537351_1.fastq.gz | Fastqsanger.gz |
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Project description:Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells. This study conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. We found that chromatin domains and looping genes’ strength have drastically changed during the 3D culture growth, although we identified very similar numbers of TADs and looping genes. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected Hippo relevant pathways genes with enhanced looping in breast cancer patient tissues’ organoid. Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer.
2021-09-29 | GSE165570 | GEO
Project description:Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells. This study conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. We found that chromatin domains and looping genes’ strength have drastically changed during the 3D culture growth, although we identified very similar numbers of TADs and looping genes. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected Hippo relevant pathways genes with enhanced looping in breast cancer patient tissues’ organoid. Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer.
2021-09-29 | GSE165571 | GEO
Project description:Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance
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Project description:Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance [RNA-Seq]
| PRJNA695074 | ENA
Project description:Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.
2020-12-01 | GSE144377 | GEO
Project description:Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.
2020-12-01 | GSE144378 | GEO
Project description:Spheroids are 3D multi-cell aggregates formed in non-addherent culture conditions. In ovarian cancer (OC), they serve as a vehicle for cancer cell dissemination in the peritoneal cavity. We investigated genes and networks upregulated in three dimensional (3D) versus two-dimensional (2D) culture conditions by Affymetrix gene expression profiling and identified ALDH1A1, a cancer stem cell marker as being upregulated in OC spheroids. Network analysis confirmed ALDH1A1 upregulation in spheroids in direct connection with elements of the beta-catenin pathway. A parallel increase in the expression levels of beta-catenin and ALDH1A1 was demonstrated in spheroids vs. monolayers an in successive spheroid generations by using OC cell liness and primary OC cells. The percentage of Aldefluor positive cells was significantly higher in spheroids vs. monolayers in IGROV1, A2780, SKOV3, and primary OC cells. B-catenin knock-down decreased ALDH1A1 expression and chromatin immunoprecipitation demonstrated that beta-catenin directly binds to the ALDH1A1 promoter. Both siRNA mediated beta-catenin knock-down and a novel ALDH1A1 small molecule enzymatic inhibitor described here for the first time, decreased the number of OC spheroids (p<0.001) and cell viability. These data strongly support the role of beta-catenin regulated ALDH1A1 in the maintenance of OC spheroids and of a stem cell phenotype and propose new ALDH1A1 inhibitors targeting this cell population. Different gene profiles were observed in ovarian cancer spheroids versus ovarian cancer monolayers. Nine samples were analyzed in triplicate. Each group is a reference.
2014-01-03 | E-GEOD-53759 | biostudies-arrayexpress
Project description:Endocrine therapy resistance invariably develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine resistant breast cancer cells and that the differential interactions are enriched for genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. Importantly, new 3D chromatin interactions often occur coincidently with hypermethylation and loss of ER binding. Additionally, alterations in active (A-type) and inactive (B-type) chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.
2019-12-11 | GSE118712 | GEO
Project description:Here we investigate the impact of epigenetic therapy with Decitabine in endocrine-resistant ER+ breast cancer by using patient-derived xenograft (PDX) models. Decitabine treatment restrained tumour growth, inhibited cell proliferation and resulted in significant loss of DNA methylation, particularly at enhancers and repetitive elements. Systematic integration of matched in situ Hi-C / PCHi-C, EPIC, RNA-seq and ChIP–seq datasets revealed widespread differences in epigenome regulation and enhancer-promoter communication with Decitabine. We find that loss of DNA methylation with Decitabine strongly affects the open (A) and closed (B) compartment structure and TAD boundary insulation. Our study identified and focused on key DNA methylation-dependent, enhancer ER binding sites that are activated in Decitabine-treated PDX tumours, enabling direct interactions between promoters and multiple distal enhancers, inducing expression of ER target genes and pathways. Overall, we demonstrate that epigenetic therapy inhibits tumour progression through to rewiring of ER-mediated 3D chromatin interactions and transcriptome programs. Our findings suggest that targeting the 3D epigenome with epigenetic therapies represents a promising strategy for anti-cancer treatment in ER+ endocrine resistant breast cancer patients.
2023-07-24 | GSE237768 | GEO
Project description:Here we investigate the impact of epigenetic therapy with Decitabine in endocrine-resistant ER+ breast cancer by using patient-derived xenograft (PDX) models. Decitabine treatment restrained tumour growth, inhibited cell proliferation and resulted in significant loss of DNA methylation, particularly at enhancers and repetitive elements. Systematic integration of matched in situ Hi-C / PCHi-C, EPIC, RNA-seq and ChIP–seq datasets revealed widespread differences in epigenome regulation and enhancer-promoter communication with Decitabine. We find that loss of DNA methylation with Decitabine strongly affects the open (A) and closed (B) compartment structure and TAD boundary insulation. Our study identified and focused on key DNA methylation-dependent, enhancer ER binding sites that are activated in Decitabine-treated PDX tumours, enabling direct interactions between promoters and multiple distal enhancers, inducing expression of ER target genes and pathways. Overall, we demonstrate that epigenetic therapy inhibits tumour progression through to rewiring of ER-mediated 3D chromatin interactions and transcriptome programs. Our findings suggest that targeting the 3D epigenome with epigenetic therapies represents a promising strategy for anti-cancer treatment in ER+ endocrine resistant breast cancer patients.
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