Aggressive PDACs show hypomethylation of repetitive elements and the execution of an intrinsic IFN program linked to a ductal cell-of-origin

Elisa Espinet, Zuguang Gu, Charles D Imbusch, Nathalia A Giese, Magdalena Buscher, Mariam Safavi, Silke Weisenburger, Corinna Klein, Vanessa Vogel, Mattia Falcone, Jacob Insua-Rodriguez, Manuel Reitberger, Vera Thiel, Steffi O Kossi, Alexander Muckenhuber, Karnjit Sarai, Alex Yl Lee, Elyne Backx, Soheila Zarei, Matthias M GaidaManuel Rodriguez-Paredes, Elisa Donato, Hsi-Yu Yen, Roland Eils, Matthias Schlesner, Nicole Pfarr, Thilo Hackert, Christoph Plass, Benedikt Brors, Katja Steiger, Dieter Weichenhan, H Efsun Arda, Ilse Rooman, Janel L Kopp, Oliver Strobel, Wilko Weichert, Martin R Sprick, Andreas Trumpp

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46 Citaten (Scopus)
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Samenvatting

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylation low tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylation low/IFNsign high and Methylation high/IFNsign low PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived Kras G12D/ Trp53 -/- mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylation low/IFNsign high subtype potentially targetable by agents blocking intrinsic IFN signaling. SIGNIFICANCE: The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity.

Originele taal-2English
Pagina's (van-tot)638-659
Aantal pagina's22
TijdschriftCancer discovery
Volume11
Nummer van het tijdschrift3
Vroegere onlinedatum15 okt 2020
DOI's
StatusPublished - mrt 2021

Bibliografische nota

©2020 American Association for Cancer Research.

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