The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
Journal article, 2018

Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number rofiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

Trametinib

Neuroendocrine tumour

Cell lines

Inhibitor screening

Exome sequencing

Immunophenotyping

Copy number alterations

Vorinostat

GEPNET

Author

Tobias Hofving

University of Gothenburg

Yvonne Arvidsson

University of Gothenburg

Bilal Almobarak

University of Gothenburg

Linda Inge

University of Gothenburg

Roswitha Pfragner

Medical University of Graz

Marta Persson

University of Gothenburg

Göran Stenman

University of Gothenburg

Erik Kristiansson

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Viktor Johanson

Sahlgrenska Academy

Ola Nilsson

University of Gothenburg

Endocrine-Related Cancer

1351-0088 (ISSN)

Vol. 25 3 367-380

Subject Categories

Cell Biology

Immunology in the medical area

Medical Genetics

DOI

10.1530/ERC-17-0445

More information

Latest update

4/4/2018 6