title: Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens.
abstract: BACKGROUND
  Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC.
  
  
  METHODS
  Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression.
  
  
  RESULTS
  Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines.
  
  
  CONCLUSIONS
  The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Dustin M
authors.initials: DM
authors.lastname: Walters
authors.forename: Jayme B
authors.initials: JB
authors.lastname: Stokes
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Adair
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stelow
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Borgman
authors.forename: Bryce T
authors.initials: BT
authors.lastname: Lowrey
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xin
authors.forename: Edik M
authors.initials: EM
authors.lastname: Blais
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Jason A
authors.initials: JA
authors.lastname: Papin
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Parsons
authors.forename: Todd W
authors.initials: TW
authors.lastname: Bauer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051901:Smad4 Protein / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D016207:Cytokines; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; D018631:ras Proteins