title: PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.
abstract: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Nilotpal
authors.initials: N
authors.lastname: Roy
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Takeuchi
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: Ruggeri
authors.affiliation: Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland.
authors.forename: David
authors.initials: D
authors.lastname: Chang
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Joey
authors.initials: J
authors.lastname: Li
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Leonhardt
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Puri
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Hoffman
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Halbrook
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
authors.affiliation: Department of Medicine/ Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Malik
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, USA.
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
mesh_terms: D061354:Acinar Cells / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000503:physiopathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein
keywords: EMT; dedifferentiation; pancreatic cancer; pancreatitis