Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility

• Published in: Gut Vol. 67; no. 3; pp. 508 - 520
• Main Authors: Knudsen, Erik S, Balaji, Uthra, Mannakee, Brian, Vail, Paris, Eslinger, Cody, Moxom, Christopher, Mansour, John, Witkiewicz, Agnieszka K
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.03.2018; BMJ Publishing Group
• Series: Original article
• Subjects: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Biodiversity; Biology; Breast cancer; Cancer therapies; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell culture; Cell cycle; Cell Line, Tumor; Chemotherapy; DNA Mutational Analysis; DNA, Neoplasm - analysis; Evolution; Evolution & development; Female; Gene Expression; Genetic analysis; Genetic diversity; Heterografts; Humans; Male; Medical prognosis; Metastases; Mice; Middle Aged; Mutation; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Patients; Phenotype; Pipelines; Polymorphism, Single Nucleotide; Preservation; Proto-Oncogene Proteins p21(ras) - genetics; Ribonucleic acid; RNA; RNA, Neoplasm - analysis; Sequence Analysis, RNA; Smad4 Protein - genetics; Solid tumors; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumors; Whole Exome Sequencing; Xenografts; ONCOGENES; CANCER GENETICS; PANCREATIC CANCER
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2016-313133

ObjectivePancreatic 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.Design27 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.ResultsThe 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.ConclusionsThese 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.