Identification of a ∆Np63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma

Xin Wang, Ana P. Kutschat, Joana Aggrey-Fynn, Feda H. Hamdan, Rondell P. Graham, Alexander Q. Wixom, Yara Souto, Swetlana Ladigan-Badura, Jennifer A. Yonkus, Amro M. Abdelrahman, Roberto Alva-Ruiz, Jochen Gaedcke, Philipp Ströbel, Robyn Laura Kosinsky, Florian Wegwitz, Patrick Hermann, Mark J. Truty, Jens T. Siveke, Stephan A. Hahn, Elisabeth HessmannSteven A. Johnsen, Zeynab Najafova

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)881-891
Number of pages11
JournalMolecular Cancer Research
Volume21
Issue number9
DOIs
StatePublished - 1 Sep 2023
Externally publishedYes

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