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Using insertional mutagenesis to identify breast cancer drivers and therapy resistance genes in mice = Insertie mutagenese voor het identificeren van genen betrokken bij de ontwikkeling van borsttumoren en therapie resistentie in muizen
In this thesis, we used genetically engineered mouse models to identify genes and pathways that are involved in ILC formation and in the development of resistance to FGFR-targeted therapy. These mice carry conditional alleles of Cdh1, which result in the inactivation of the cell-adhesion molecule E-cadherin when Cre-recombinase is expressed. As mice with mammary-specific inactivation of E-cadherin alone were not prone to develop mammary tumors, they were used to investigate the contribution of additional genetic mutations to the development of ILCs using different genetic approaches. Firstly, we used non-germline modeling to study the role of PI3K-AKT signaling in the development of ILCs by performing intraductal injections of high-titer lentiviruses. Secondly, we employed a Sleeping Beauty (SB)-based insertional mutagenesis screen in conditional Cdh1 knockout mice to identify novel genes and pathways involved in the development of ILCs. We show that active transposon...
Show moreIn this thesis, we used genetically engineered mouse models to identify genes and pathways that are involved in ILC formation and in the development of resistance to FGFR-targeted therapy. These mice carry conditional alleles of Cdh1, which result in the inactivation of the cell-adhesion molecule E-cadherin when Cre-recombinase is expressed. As mice with mammary-specific inactivation of E-cadherin alone were not prone to develop mammary tumors, they were used to investigate the contribution of additional genetic mutations to the development of ILCs using different genetic approaches. Firstly, we used non-germline modeling to study the role of PI3K-AKT signaling in the development of ILCs by performing intraductal injections of high-titer lentiviruses. Secondly, we employed a Sleeping Beauty (SB)-based insertional mutagenesis screen in conditional Cdh1 knockout mice to identify novel genes and pathways involved in the development of ILCs. We show that active transposon mutagenesis drives ILC formation and analysis of common insertion sites in SB-induced tumors identified a mutually exclusive group of four genes, of which three are frequently aberrated in human ILCs. Lastly, we used active mobilization of transposons in transplanted mouse ILCs to identify genes involved in acquiring resistance to the FGFR inhibitor AZD4547.
Show less- All authors
- Kas, S.M.
- Supervisor
- Jonkers, J.
- Committee
- Irth, H.; Bouwstra, J.; Devilee, P.; Dijke, P. ten; Neefjes, J.; Bernards, R.; Borst, J.; Adams, D.
- Qualification
- Doctor (dr.)
- Awarding Institution
- Leiden Academic Centre for Drug Research (LACDR) , Faculty of Science , Leiden University
- Date
- 2018-11-14
- ISBN (print)
- 9789493014848
Funding
- Sponsorship
- Netherlands Organization for Scientific Research (NWO: Cancer Systems Biology Center) and the European Research Council (ERC Synergy project CombatCancer).