title: Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model.
abstract: Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a+/Cre; Hes1fl/fl). Using this model, we studied the role of Hes1 in both acinar cell plasticity and pancreatic regeneration after caerulein-induced pancreatitis and in KrasG12D-driven PDAC development. We show that, although pancreatic development is not perturbed on the deletion of Hes1, terminal acinar differentiation in the adult pancreas is compromised. Moreover, the loss of Hes1 leads to the impaired regeneration of the exocrine compartment, accelerated fatty metaplasia, and persistent ADM after acute caerulein-induced pancreatitis. In KrasG12D-driven carcinogenesis, Hes1 ablation resulted in increased ADM, decreased formation of high-grade pancreatic intraepithelial neoplasias, and accelerated development of PDAC with shortened survival time. In conclusion, Hes1 plays a key role in acinar cell integrity and plasticity on cellular insults. Furthermore, Hes1 is an essential component of the pancreatic intraepithelial neoplasias-to-PDAC route in KrasG12D-driven mouse pancreatic carcinogenesis.
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Hidalgo-Sastre
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Roxanne L
authors.initials: RL
authors.lastname: Brodylo
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Lubeseder-Martellato
authors.affiliation: Department of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Comparative Experimental Pathology Unit, Institute for General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Lee
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: von Figura
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grünwald
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Suyang
authors.initials: S
authors.lastname: Zhong
authors.affiliation: German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Marija
authors.initials: M
authors.lastname: Trajkovic-Arsic
authors.affiliation: German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Neff
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. Electronic address: j.siveke@dkfz.de.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D061354:Acinar Cells / Q000473:pathology / Q000502:physiology; D000818:Animals; D063646:Carcinogenesis; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D000066670:Cell Plasticity; D002108:Ceruletide / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008679:Metaplasia; D051379:Mice; D010179:Pancreas / Q000473:pathology / Q000502:physiology; D046790:Pancreas, Exocrine / Q000473:pathology / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C489734:Hes1 protein, mouse; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; D002108:Ceruletide