title: Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease with the worst survival rate of common solid tumours. Preclinical models that accurately reflect the genetic and biological diversity of PDAC will be important for delineating features of tumour biology and therapeutic vulnerabilities.
  
  
  
  27 primary PDAC tumours were employed for genetic analysis and development of tumour models. Tumour tissue was used for derivation of xenografts and cell lines. Exome sequencing was performed on the originating tumour and developed models. RNA sequencing, histological and functional analyses were employed to determine the relationship of the patient-derived models to clinical presentation of PDAC.
  
  
  
  The cohort employed captured the genetic diversity of PDAC. From most cases, both cell lines and xenograft models were developed. Exome sequencing confirmed preservation of the primary tumour mutations in developed cell lines, which remained stable with extended passaging. The level of genetic conservation in the cell lines was comparable to that observed with patient-derived xenograft (PDX) models. Unlike historically established PDAC cancer cell lines, patient-derived models recapitulated the histological architecture of the primary tumour and exhibited metastatic spread similar to that observed clinically. Detailed genetic analyses of tumours and derived models revealed features of ex vivo evolution and the clonal architecture of PDAC. Functional analysis was used to elucidate therapeutic vulnerabilities of relevance to treatment of PDAC.
  
  
  
  These data illustrate that with the appropriate methods it is possible to develop cell lines that maintain genetic features of PDAC. Such models serve as important substrates for analysing the significance of genetic variants and create a unique biorepository of annotated cell lines and xenografts that were established simultaneously from same primary tumour. These models can be used to infer genetic and empirically determined therapeutic sensitivities that would be germane to the patient.
authors.affiliation: University of Arizona Department of Medicine, University of Arizona, Tucson, Arizona, USA.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.|McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Uthra
authors.initials: U
authors.lastname: Balaji
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Mannakee
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Paris
authors.initials: P
authors.lastname: Vail
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Cody
authors.initials: C
authors.lastname: Eslinger
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Moxom
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mansour
authors.affiliation: University of Arizona Department of Medicine, University of Arizona, Tucson, Arizona, USA.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.|McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|University of Arizona Department of Pathology, University of Arizona, Tucson, Arizona, USA.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis*; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012334:RNA, Neoplasm / Q000032:analysis*; D017423:Sequence Analysis, RNA; D051901:Smad4 Protein / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D012334:RNA, Neoplasm; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CANCER GENETICS; ONCOGENES; PANCREATIC CANCER