Researchers have identified mechanisms of genetic cooperation at the root of liver tumours.
We have applied a genetic method to randomly mutate large numbers of genes in the context of a mouse model with increased RTK levels, predisposed to develop liver cancer. We identified mechanisms that accelerate tumour formation in cooperation with enhanced RTK levels. The wide array of cellular functions among these cooperators illustrates an extraordinary capability of RTKs to render the liver more vulnerable to additional alterations, by priming cells for tumour initiation.
Evaluating the landscape of gene cooperativity with RTKs in liver tumorigenesis
Summary. The variety of alterations found in hepatocellular carcinoma (HCC) challenges the identification of functionally relevant genes and their combinatorial actions in tumorigenesis. Deregulation of Receptor Tyrosine Kinases (RTKs) is frequent in HCC, yet little is known about the molecular events that cooperate with RTKs and whether these cooperative events play an active role at the root of liver tumorigenesis. A forward genetic screen was performed using Sleeping Beauty transposon insertional mutagenesis to accelerate liver tumour formation in a genetic context in which subtly increased MET RTK levels predispose towards tumorigenesis. Systematic sequencing of tumours identified common transposon insertion sites, thus uncovering putative RTK cooperators for liver cancer. Bioinformatic analyses were applied to transposon outcomes and human HCC datasets. In vitro and in vivo functional screens were performed to assess the relevance of distinct cooperative modes to confer tumorigenic properties with RTKs.
We identified 275 genes, most of which are altered in HCC patients. Unexpectedly, these genes are not restricted to a small set of pathway/cellular processes, but cover a large spectrum of cellular functions, including signalling, metabolism, chromatin remodelling, mRNA degradation, proteasome, ubiquitination, cell cycle regulation, and chromatid segregation. We validated 15 tumour suppressor candidates, as shRNA-mediated targeting confers tumorigenicity to RTK-sensitized cells, but not to cells with basal RTK levels. This demonstrates that the context of enhanced RTK levels is essential for their action in tumour initiation. Our study identifies unanticipated genetic interactions underlying gene cooperativity with RTKs in HCC. Moreover, these results show how subtly increased levels of wild-type RTKs provide a permissive context allowing a large spectrum of deregulated mechanisms to initiate liver cancer.
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Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis
Yannan Fan1,#, Sehrish K. Bazai1,#, Fabrice Daian1, Maria Arechederra1, Sylvie Richelme1, Nuri A. Temiz2, Annie Yim3, Bianca H. Habermann1, Rosanna Dono1, David A. Largaespada2, and Flavio Maina1,*
1 Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM) UMR 7288, Parc Scientifique de Luminy, Marseille (France)
2 Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
3 Computational Biology Group, Max Planck Institute of Biochemistry, Martinsried (Germany)
Journal of Hepatology 2019 Mar;70(3):470-482. doi: 10.1016/j.jhep.2018.11.027.
Contact: Flavio Maina – firstname.lastname@example.org