Enhancer reprogramming promotes pancreatic cancer progression and metastasis
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ABSTRACT:
PROVIDER: PRJNA388090 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Enhancer reprogramming promotes pancreatic cancer progression and metastasis [ChIP-seq]
| PRJNA387949 | ENA
Project description:Enhancer reprogramming promotes pancreatic cancer progression and metastasis [RNA-seq]
| PRJNA388127 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during each stage of PDA progression. This approach revealed that the metastatic transition is accompanied by massive, and recurrent alterations in enhancer activity. We implicate the transcription factors FOXA1 and GATA5 as drivers of enhancer activation in this system, a mechanism that we show renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. FOXA1 and GATA5 were found to activate a foregut endoderm transcriptional program in PDA cells, without altering genes associated with the epithelial-to- mesenchymal transition. Collectively, our study implicates FOXA1/GATA5 upregulation, enhancer reprogramming, and a novel retrograde developmental transition in PDA progression and metastasis.
2017-07-31 | GSE99284 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during each stage of PDA progression. This approach revealed that the metastatic transition is accompanied by massive, and recurrent alterations in enhancer activity. We implicate the transcription factors FOXA1 and GATA5 as drivers of enhancer activation in this system, a mechanism that we show renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. FOXA1 and GATA5 were found to activate a foregut endoderm transcriptional program in PDA cells, without altering genes associated with the epithelial-to- mesenchymal transition. Collectively, our study implicates FOXA1/GATA5 upregulation, enhancer reprogramming, and a novel retrograde developmental transition in PDA progression and metastasis.
2017-07-31 | GSE99275 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during each stage of PDA progression. This approach revealed that the metastatic transition is accompanied by massive, and recurrent alterations in enhancer activity. We implicate the transcription factors FOXA1 and GATA5 as drivers of enhancer activation in this system, a mechanism that we show renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. FOXA1 and GATA5 were found to activate a foregut endoderm transcriptional program in PDA cells, without altering genes associated with the epithelial-to- mesenchymal transition. Collectively, our study implicates FOXA1/GATA5 upregulation, enhancer reprogramming, and a novel retrograde developmental transition in PDA progression and metastasis.
2017-07-31 | GSE99310 | GEO
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. BS-Seq of 4 patients (A13, A38, A124 and A125). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets). Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates. Patient A124 included 2 primary tumors and 1 normal pancreas.
2016-10-24 | E-GEOD-63123 | biostudies-arrayexpress
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. RNA-Seq of 2 patients (A13 and A38). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO control samples. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.
2016-10-24 | E-GEOD-63124 | biostudies-arrayexpress
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. Chip-Seq (K27Me3, K36Me3, K9Me2/3, K4Me3 and K27Ac) of 2 patients (A13 and A38) and HPDE cell line. Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO samples for lung matastasis. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.
2016-10-24 | E-GEOD-63125 | biostudies-arrayexpress
Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
2019-05-24 | MSV000083857 | MassIVE
Project description: Not available
| S-EPMC5726277 | biostudies-literature