TY  - JOUR
AU  - Wang, Xin
AU  - Kutschat, Ana P
AU  - Aggrey-Fynn, Joana
AU  - Hamdan, Feda H
AU  - Graham, Rondell P
AU  - Wixom, Alexander Q
AU  - Souto, Yara
AU  - Ladigan-Badura, Swetlana
AU  - Yonkus, Jennifer A
AU  - Abdelrahman, Amro M
AU  - Alva-Ruiz, Roberto
AU  - Gaedcke, Jochen
AU  - Ströbel, Philipp
AU  - Kosinsky, Robyn Laura
AU  - Wegwitz, Florian
AU  - Hermann, Patrick
AU  - Truty, Mark J
AU  - Siveke, Jens
AU  - Hahn, Stephan A
AU  - Hessmann, Elisabeth
AU  - Johnsen, Steven A
AU  - Najafova, Zeynab
TI  - Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma.
JO  - Molecular cancer research
VL  - 21
IS  - 9
SN  - 1541-7786
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2023-01810
SP  - 881 - 891
PY  - 2023
AB  - 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 patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, 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.Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.
KW  - Humans
KW  - Precision Medicine
KW  - Pancreatic Neoplasms: pathology
KW  - Carcinoma, Pancreatic Ductal: pathology
KW  - RNA
KW  - Gene Expression Regulation, Neoplastic
KW  - RNA (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37279184
DO  - DOI:10.1158/1541-7786.MCR-22-0916
UR  - https://inrepo02.dkfz.de/record/282521
ER  -