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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Bibliographic Details
Published in:	Cancer discovery Vol. 11; no. 3; p. 638
Main Authors:	Espinet, Elisa, Gu, Zuguang, Imbusch, Charles D, Giese, Nathalia A, Büscher, Magdalena, Safavi, Mariam, Weisenburger, Silke, Klein, Corinna, Vogel, Vanessa, Falcone, Mattia, Insua-Rodríguez, Jacob, Reitberger, Manuel, Thiel, Vera, Kossi, Steffi O, Muckenhuber, Alexander, Sarai, Karnjit, Lee, Alex Y L, Backx, Elyne, Zarei, Soheila, Gaida, Matthias M, Rodríguez-Paredes, Manuel, Donato, Elisa, Yen, Hsi-Yu, Eils, Roland, Schlesner, Matthias, Pfarr, Nicole, Hackert, Thilo, Plass, Christoph, Brors, Benedikt, Steiger, Katja, Weichenhan, Dieter, Arda, H Efsun, Rooman, Ilse, Kopp, Janel L, Strobel, Oliver, Weichert, Wilko, Sprick, Martin R, Trumpp, Andreas
Format:	Journal Article
Language:	English
Published:	United States 01-03-2021
Subjects:	Carcinoma, Pancreatic Ductal - etiology Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - mortality Carcinoma, Pancreatic Ductal - pathology Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism CpG Islands Disease Progression Disease Susceptibility DNA Methylation Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Interferons - metabolism Models, Biological Pancreatic Neoplasms - etiology Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - mortality Pancreatic Neoplasms - pathology Prognosis Repetitive Sequences, Nucleic Acid Reproducibility of Results Signal Transduction Transcriptome Tumor Microenvironment - genetics
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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. Methylation 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 /IFNsign and Methylation /IFNsign PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived / 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 /IFNsign 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. .
ISSN:	2159-8290
DOI:	10.1158/2159-8290.CD-20-1202