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

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. Clust...

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Main Authors: Espinet, Elisa (Author) , Gu, Zuguang (Author) , Imbusch, Charles (Author) , Giese, Nathalia (Author) , Büscher, Magdalena (Author) , Safavi, Mariam (Author) , Weisenburger, Silke (Author) , Klein, Corinna (Author) , Vogel, Vanessa (Author) , Falcone, Mattia (Author) , Insua-Rodríguez, Jacob (Author) , Reitberger, Manuel (Author) , Thiel, Vera (Author) , Kossi, Steffi O. (Author) , Muckenhuber, Alexander (Author) , Sarai, Karnjit (Author) , Lee, Alex YL (Author) , Backx, Elyne (Author) , Zarei, Soheila (Author) , Gaida, Matthias (Author) , Rodríguez Paredes, Manuel (Author) , Donato, Elisa (Author) , Yen, Hsi-Yu (Author) , Eils, Roland (Author) , Schlesner, Matthias (Author) , Pfarr, Nicole (Author) , Hackert, Thilo (Author) , Plass, Christoph (Author) , Brors, Benedikt (Author) , Steiger, Katja (Author) , Weichenhan, Dieter (Author) , Arda, H. Efsun (Author) , Rooman, Ilse (Author) , Kopp, Janel L. (Author) , Strobel, Oliver (Author) , Weichert, Wilko (Author) , Sprick, Martin (Author) , Trumpp, Andreas (Author)
Format: Article (Journal)
Language:English
Published: 2021
In: Cancer discovery
Year: 2021, Volume: 11, Issue: 3, Pages: 638-659
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-20-1202
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1158/2159-8290.CD-20-1202
Verlag, lizenzpflichtig, Volltext: https://cancerdiscovery.aacrjournals.org/content/early/2020/10/09/2159-8290.CD-20-1202
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Author Notes: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. Gaida, Manuel 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 and Andreas Trumpp
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Summary: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. Methylationlow tumors are characterized by higher expression of endogenous retroviral (ERV) transcripts and dsRNA sensors which leads to a cell intrinsic activation of an interferon signature (IFNsign). This results in a pro-tumorigenic microenvironment and poor patient outcome. Methylationlow/IFNsignhigh and Methylationhigh/IFNsignlow PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived KrasG12D/Trp53-/- mouse PDACs show higher expression of IFNsign compared to acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylationlow/IFNsignhigh subtype potentially targetable by agents blocking intrinsic IFN-signaling.
Item Description:Published first October 15, 2020
Gesehen am 16.10.2020
Physical Description:Online Resource
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-20-1202

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