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| Status |
Public on Sep 19, 2023 |
| Title |
Identification of a ΔNp63-dependent Basal-like A Subtype-specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for both patient stratification and for choice of therapy. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft (PDX) models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analysis revealed a basal-like A subtype-specific transcribed enhancer program (B-STEP) in PDAC characterized by enhancer RNA (eRNA) production that is associated with higher chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histological approach for PDAC patient stratification by performing RNA in situ hybridization analyses for subtype-specific eRNAs on pathological tissue samples. Thus, the finding in this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single cell level in complex, heterogeneous, primary tumor material.
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| Overall design |
mRNA-Seq was performed in a cohort of pancreatic ductal adenocarcinoma (PDAC) patient-derived xenografts (PDX) to determine the represenation of PDAC subtypes associated gene signatures. Moreover, to investigate the function of ∆NP63 in regulating the PDAC-subytpe specific gene expression, mRNA-Seq in L3.6pl cells was performed following P63 knockdown. mRNA-Seq with JQ1 treatment in L3.6pl cells was additionally utilized to analyze the effect of BET protein inhibition on ∆NP63- regulated transcriptional program.
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| Contributor(s) |
Najafova Zb, Johnsen SA |
| Citation(s) |
37279184 |
| |
| Submission date |
Sep 14, 2022 |
| Last update date |
Sep 19, 2023 |
| Contact name |
Steven A. Johnsen |
| Organization name |
Robert Bosch Center for Tumor Diseases
|
| Lab |
Molecular Cancer Epigenetics
|
| Street address |
Auerbachstraße 112
|
| City |
Stuttgart |
| State/province |
BW |
| ZIP/Postal code |
70376 |
| Country |
Germany |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (26)
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| This SubSeries is part of SuperSeries: |
| GSE213397 |
Identification of a ΔNp63-dependent Basal-like A Subtype-specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma |
|
| Relations |
| BioProject |
PRJNA880839 |
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