2. Academic Validation
  3. AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53

  • Gastroenterology. 2021 Nov;161(5):1601-1614.e23. doi: 10.1053/j.gastro.2021.07.030.
Zhiheng Zhang 1,  Hongzhen Li 2,  Yibin Deng 3,  Kathleen Schuck 4,  Susanne Raulefs 1,  Nadja Maeritz 1,  Yuanyuan Yu 4,  Torsten Hechler 5,  Andreas Pahl 5,  Vanesa Fernández-Sáiz 6,  Yuan Wan 7,  Guosheng Wang 7,  Thomas Engleitner 8,  Rupert Öllinger 9,  Roland Rad 9,  Maximilian Reichert 10,  Kalliope N Diakopoulos 11,  Verena Weber 1,  Jingjing Li 12,  Shanshan Shen 12,  Xiaoping Zou 12,  Jörg Kleeff 13,  Andre Mihaljevic 4,  Christoph W Michalski 4,  Hana Algül 11,  Helmut Friess 1,  Bo Kong 14
Affiliations

Affiliations

  • 1 Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
  • 2 Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 4 Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
  • 5 Heidelberg Pharma Research GmbH, Ladenburg, Germany.
  • 6 Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Center for Translational Cancer Research, Technische Universität München, Munich, Germany.
  • 7 The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York.
  • 8 Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany.
  • 9 Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany.
  • 10 Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 11 Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany.
  • 12 Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China.
  • 13 Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • 14 Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany. Electronic address: bo.kong@uniklinik-ulm.de.
PMID: 34303658 DOI: 10.1053/j.gastro.2021.07.030
Abstract

Background & aims: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.

Methods: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex.

Results: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various Cancer types.

Conclusions: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

Keywords

Agr2; Hexapeptide; Metaplastic; Neoplastic; Pancreatic Cancer.

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