title: Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation.
abstract: The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Drosos
authors.affiliation: Department of Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Leena
authors.initials: L
authors.lastname: Paul
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Emin
authors.initials: E
authors.lastname: Kuliyev
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Means
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Jerold
authors.initials: J
authors.lastname: Rehg
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: David B
authors.initials: DB
authors.lastname: Finkelstein
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. Electronic address: beatriz.sosa-pineda@northwestern.edu.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sosa-Pineda
mesh_terms: D061354:Acinar Cells / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002108:Ceruletide / Q000008:administration & dosage; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008679:Metaplasia / Q000235:genetics / Q000473:pathology; D051379:Mice; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D002108:Ceruletide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)