title: Transcriptional dissection of pancreatic tumors engrafted in mice.
abstract: BACKGROUND
  Engraftment of primary pancreas ductal adenocarcinomas (PDAC) in mice to generate patient-derived xenograft (PDX) models is a promising platform for biological and therapeutic studies in this disease. However, these models are still incompletely characterized. Here, we measured the impact of the murine tumor environment on the gene expression of the engrafted human tumoral cells.
  
  
  METHODS
  We have analyzed gene expression profiles from 35 new PDX models and compared them with previously published microarray data of 18 PDX models, 53 primary tumors and 41 cell lines from PDAC. The results obtained in the PDAC system were further compared with public available microarray data from 42 PDX models, 108 primary tumors and 32 cell lines from hepatocellular carcinoma (HCC). We developed a robust analysis protocol to explore the gene expression space. In addition, we completed the analysis with a functional characterization of PDX models, including if changes were caused by murine environment or by serial passing.
  
  
  RESULTS
  Our results showed that PDX models derived from PDAC, or HCC, were clearly different to the cell lines derived from the same cancer tissues. Indeed, PDAC- and HCC-derived cell lines are indistinguishable from each other based on their gene expression profiles. In contrast, the transcriptomes of PDAC and HCC PDX models can be separated into two different groups that share some partial similarity with their corresponding original primary tumors. Our results point to the lack of human stromal involvement in PDXs as a major factor contributing to their differences from the original primary tumors. The main functional differences between pancreatic PDX models and human PDAC are the lower expression of genes involved in pathways related to extracellular matrix and hemostasis and the up- regulation of cell cycle genes. Importantly, most of these differences are detected in the first passages after the tumor engraftment.
  
  
  CONCLUSIONS
  Our results suggest that PDX models of PDAC and HCC retain, to some extent, a gene expression memory of the original primary tumors, while this pattern is not detected in conventional cancer cell lines. Expression changes in PDXs are mainly related to pathways reflecting the lack of human infiltrating cells and the adaptation to a new environment. We also provide evidence of the stability of gene expression patterns over subsequent passages, indicating early phases of the adaptation process.
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Martinez-Garcia
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Juan
authors.affiliation: SIB Swiss Institute of Bioinformatics, Vital-IT Group, 1015 Lausanne, Switzerland ; Institute of Microbiology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rausell
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Baños
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Camino
authors.initials: C
authors.lastname: Menéndez
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Lopez-Casas
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
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