The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
Artikel i vetenskaplig tidskrift, 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

Författare

Tobias Hofving

Göteborgs universitet

Yvonne Arvidsson

Göteborgs universitet

Bilal Almobarak

Göteborgs universitet

Linda Inge

Göteborgs universitet

Roswitha Pfragner

Medizinische Universität Graz

Marta Persson

Göteborgs universitet

Göran Stenman

Göteborgs universitet

Erik Kristiansson

Chalmers, Matematiska vetenskaper, Tillämpad matematik och statistik

Viktor Johanson

Sahlgrenska akademin

Ola Nilsson

Göteborgs universitet

Endocrine-Related Cancer

1351-0088 (ISSN)

Vol. 25 367-380

Ämneskategorier

Cellbiologi

Immunologi inom det medicinska området

Medicinsk genetik

DOI

10.1530/ERC-17-0445