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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

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
Elisa Espinet
1Division of Stem Cells and Cancer, German Cancer Research Center
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  • ORCID record for Elisa Espinet
Zuguang Gu
2Molecular Genome Analysis, German Cancer Research Center
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Charles D. Imbusch
3Division of Applied Bioinformatics, DKFZ
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Nathalia A Giese
4Department of Surgery, University Hospital Heidelberg
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Magdalena Buscher
1Division of Stem Cells and Cancer, German Cancer Research Center
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Mariam Safavi
1Division of Stem Cells and Cancer, German Cancer Research Center
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Silke Weisenburger
1Division of Stem Cells and Cancer, German Cancer Research Center
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Corinna Klein
5HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental, HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental
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Vanessa Vogel
6Institut fur Pathologie, Institut fur Pathologie
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Mattia Falcone
7Stem Cells and Cancer, DKFZ
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Jacob Insua-Rodriguez
8Department of Physiology & Biophysics and Department of Biological Chemistry, University of California, Irvine
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Manuel Reitberger
9Division of Stem Cells and Cancer, DKFZ
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Vera Thiel
10Hi-Stem, DKFZ
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Steffi O. Kossi
11Heidelberg Institute for Stem Cell Technology and Experimental Medicine
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Alexander Muckenhuber
12Technische Universitat Munchen
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Karnjit Sarai
13University of British Columbia
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Alex YL Lee
13University of British Columbia
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Elyne Backx
14Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel
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Soheila Zarei
15Cellular and Physiological Sciences, University of British Columbia
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Matthias M. Gaida
16Institute of Pathology, University Hospital Mainz
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Manuel Rodriguez-Paredes
17Division of Epigenetics, German Cancer Research Center
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Elisa Donato
1Division of Stem Cells and Cancer, German Cancer Research Center
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Hsi-Yu Yen
18Institute of Pathology, Technical University Munich
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Roland Eils
19Berlin Institute of Health
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Matthias Schlesner
20Bioinformatics and Omics Data Analytics, German Cancer Research Center
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Nicole Pfarr
18Institute of Pathology, Technical University Munich
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Thilo Hackert
4Department of Surgery, University Hospital Heidelberg
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Christoph Plass
21Cancer Epigenomics, German Cancer Research Center, DKFZ
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Benedikt Brors
22Department of Applied Bioinformatics, German Cancer Research Center
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Katja Steiger
23Institute of Pathology, Technische Universitat Munchen
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Dieter Weichenhan
24Cancer Epigenomics, DKFZ Heidelberg
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H. Efsun Arda
25National Institutes of Health
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Ilse Rooman
26Oncology Research Centre, Vrije Universiteit Brussel
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Janel L Kopp
27Cellular & Physiological Sciences, University of British Columbia
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Oliver Strobel
28Department of General, Visceral und Transplantation Surgery, University Hospital Heidelberg
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Wilko Weichert
29Institute of General Pathology and Pathological Anatomy, Technical University Munich
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Martin R. Sprick
1Division of Stem Cells and Cancer, German Cancer Research Center
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Andreas Trumpp
1Division of Stem Cells and Cancer, German Cancer Research Center
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  • For correspondence: a.trumpp@dkfz.de
DOI: 10.1158/2159-8290.CD-20-1202
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Abstract

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.

  • Received August 18, 2020.
  • Revision received September 24, 2020.
  • Accepted September 25, 2020.
  • Copyright ©2020, American Association for Cancer Research.
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This OnlineFirst version was published on October 15, 2020
doi: 10.1158/2159-8290.CD-20-1202

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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
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
Cancer Discov October 15 2020 DOI: 10.1158/2159-8290.CD-20-1202

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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
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
Cancer Discov October 15 2020 DOI: 10.1158/2159-8290.CD-20-1202
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