title: Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization.
abstract: The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Takano
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; II. Medizinische Klinik, Technical University of Munich, Munich 81675, Germany;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Basil
authors.initials: B
authors.lastname: Bakir
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Koushik K
authors.initials: KK
authors.lastname: Das
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine II, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeg
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Collins
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Benoît
authors.initials: B
authors.lastname: Marchand
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hicks
authors.affiliation: Department of Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Translational Molecular Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000503:physiopathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; C082157:PRRX1 protein, human; D020033:Protein Isoforms; C489936:Prrx1 protein, mouse; D017228:Hepatocyte Growth Factor
keywords: EMT; MET; Prrx1a; Prrx1b; metastasis; pancreatic cancer