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Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

ABSTRACT: Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover novel regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194249 | GEO | 2022/02/23

REPOSITORIES: GEO

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Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity (ATAC-Seq data).

Project description:Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover novel regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.

2022-02-23 | GSE195623 | GEO

Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

Project description:Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

| PRJNA799993 | ENA

Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity (ATAC-Seq data).

Project description:Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity (ATAC-Seq data).

| PRJNA801501 | ENA

Single-cell epigenomic variability reveals functional cancer heterogeneity

Project description:Background: Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity, but is difficult to detect and assess functionally. Results: We develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high vs. low cells prospectively isolated GATA1 and GATA2 high vs. low cells. GATA high vs. low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity. Conclusion: Single-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution.

2016-12-12 | GSE76224 | GEO

p53 influences 5-FU-induced chromatin accessibility [ChIP-seq]

Project description:5-Fluorouracil (5-FU) is one of the most common drugs used in chemotherapy because of its efficacy and stability. However, 5-FU has been known to work on only 10~15% of colon cancer patients. Therefore, the study of 5-FU sensitivity study is necessary to increase the survival of colon cancer patients. p53 is one of the factors that effect on drug sensitivity. Main function of p53 has been focused on transcription activity in cell death. Numerous drug related studies show that expression of wild-type p53 increases drug sensitivity in various cancer types through inducing apoptotic signaling pathways. Currently, it has been reported that p53 has both transcriptional and non-transcriptional activities in apoptosis. However, most studies about p53 non-transcriptional activities in apoptosis are mainly focused on p53 induced mitochondrial outer membrane permeabilization, triggering the release of pro-apoptotic factors. The chromatin structure and organization have strongly attracted because of their impacts in cellular phenotypes. Recent studies have been shown that changes in chromatin accessibility affect cell phenotypes for external stimuli. Since p53 plays an important role in drug sensitivity and 5-FU is an external stimulus for cancer cells, we hypothesized that p53 may effect on 5-FU sensitivity through different regulation of chromatin accessible regions between TP53-WT and TP53-KO cells. To determine the effect of p53 on chromatin accessibility modification associated with 5-FU sensitivity, ATAC-seq and RNA-seq were performed under 5-FU treatment on TP53-WT as drug sensitive and TP53-KO as drug resistant HCT116 cells. In this study, we found that 5-FU induces chromatin accessibility in both TP53-WT and TP53-KO cells. Moreover, our results show that 5-FU induced chromatin accessibility increases expression of apoptotic genes in TP53-WT HCT116 cells through p53 non-transcriptional activity in nucleus.

2021-02-10 | GSE157950 | GEO

p53 influences 5-FU-induced chromatin accessibility [ATAC-seq]

2021-02-10 | GSE157949 | GEO

FOXA2 controls the anti-oxidant response in FH-deficient cells independent of NRF2

Project description:Hereditary Leiomyomatosis and renal cell cancer is caused by fumarate hydratase loss of heterozygosity and subsequence accumulation of fumarate. Fumarate is known to activate the anti-oxidant response and is key for cellular survival. Fumarate succinates KEAP1 which releases NRF2 to activate the antioxidant response. The role of fumarate on the global regulatory chromatin landscape is less understood. Here, by integrating chromatin accessibility and histone ChIP-seq profiles, we identify complex transcription factor networks involved in the highly remodelled chromatin landscape of FH-deficient cells. We implicate FOXA2 in the maintenance of FH-deficient cells by regulating anti-oxidant response genes and subsequent metabolic output, independent of NRF2. These results identify new redox and amino acid metabolism regulators and provide new avenues for therapeutic intervention.

2022-06-01 | ST002199 | MetabolomicsWorkbench

Pancreatic cancer prognosis is predicted by chromatin accessibility

Project description:Pancreatic cancer prognosis is predicted by chromatin accessibility

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Expression Data from 24 orthotopic tumors grown in the pancreas of mice +/- MEK inhibitor PD0325901

Project description:Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. We used microarrays to find gene expression patterns associated with drug response and also identified genes regulated by the MAP kinase pathway 6 pancreatic cell lines were injected into the pancreas of nude mice and treated either with vehicle control or PD0325901 for 12 plus 12 hours.

2013-04-04 | E-GEOD-45758 | biostudies-arrayexpress

Expression Data from 22 human pancreatic cancer cell lines grown in triplicates +/- MEK inhibitor CI-1040

Project description:Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. We used microarrays to find gene expression patterns associated with drug response and also identified genes regulated by the MAP kinase pathway 22 pancreatic cell lines were grown in culture media containing serum and either treated with vehicle control or CI-1040 for 24 hours

2013-04-04 | E-GEOD-45757 | biostudies-arrayexpress

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