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  Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis.

Fan, Y., Bazai, S. K., Daian, F., Arechederra, M., Richelme, S., Temiz, N. A., et al. (2019). Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis. Journal of Hepatology, 70(3), 470-482. doi:10.1016/j.jhep.2018.11.027.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-CE04-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-033A-8
Genre: Journal Article

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 Creators:
Fan, Yannan1, Author
Bazai, Sehrish K1, Author
Daian, Fabrice1, Author
Arechederra, Maria1, Author
Richelme, Sylvie1, Author
Temiz, Nuri A1, Author
Yim, Annie2, Author              
Habermann, Bianca H1, Author
Dono, Rosanna1, Author
Largaespada, David A1, Author
Maina, Flavio1, Author
Affiliations:
1external, ou_persistent22              
2Habermann, Bianca / Computational Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1832284              

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Free keywords: Functional screening; HCC; Hepatocellular carcinoma; Liver cancer; Mouse model; Oncogenes; Receptor tyrosine kinases; Signalling; Tumour suppressors
 Abstract: BACKGROUND & AIMS: The variety of alterations found in hepatocellular carcinoma (HCC) makes the identification of functionally relevant genes and their combinatorial actions in tumorigenesis challenging. 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.; METHODS: 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 mice to 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 (through xenografts) functional screens were performed to assess the relevance of distinct cooperative modes to the tumorigenic properties conferred by RTKs.; RESULTS: We identified 275 genes, most of which are altered in patients with HCC. 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.; CONCLUSION: 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 tumour permissive cellular environment allowing a large spectrum of deregulated mechanisms to initiate liver cancer.; LAY SUMMARY: Receptor tyrosine kinases (RTKs) are among signals frequently deregulated in patients with hepatocellular carcinoma and their deregulation confers essential biological properties to cancer cells. 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. Copyright © 2018 European Association for the Study of the Liver. All rights reserved.

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Language(s): eng - English
 Dates: 2018-12-062019-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 30529386
DOI: 10.1016/j.jhep.2018.11.027
 Degree: -

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Title: Journal of Hepatology
  Other : J. Hepatol.
Source Genre: Journal
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Publ. Info: Amsterdam : Elsevier
Pages: - Volume / Issue: 70 (3) Sequence Number: - Start / End Page: 470 - 482 Identifier: ISSN: 0168-8278
CoNE: https://pure.mpg.de/cone/journals/resource/954925485712