Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells

Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor gene...

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Main Authors:	Huijbers, Ivo J, Bin Ali, Rahmen, Pritchard, Colin, Cozijnsen, Miranda, Kwon, Min-Chul, Proost, Natalie, Song, Ji-Ying, Vries, Hilda, Badhai, Jitendra, Sutherland, Kate, Krimpenfort, Paul, Michalak, Ewa M, Jonkers, Jos, Berns, Anton
Format:	Online
Language:	English
Published:	Blackwell Publishing Ltd 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927956/

id	pubmed-3927956
recordtype	oai_dc
spelling	pubmed-39279562014-02-28 Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells Huijbers, Ivo J Bin Ali, Rahmen Pritchard, Colin Cozijnsen, Miranda Kwon, Min-Chul Proost, Natalie Song, Ji-Ying Vries, Hilda Badhai, Jitendra Sutherland, Kate Krimpenfort, Paul Michalak, Ewa M Jonkers, Jos Berns, Anton Research Article Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer. Blackwell Publishing Ltd 2014-02 2014-01-15 /pmc/articles/PMC3927956/ /pubmed/24401838 http://dx.doi.org/10.1002/emmm.201303297 Text en © 2014 The Authors. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License,which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huijbers, Ivo J Bin Ali, Rahmen Pritchard, Colin Cozijnsen, Miranda Kwon, Min-Chul Proost, Natalie Song, Ji-Ying Vries, Hilda Badhai, Jitendra Sutherland, Kate Krimpenfort, Paul Michalak, Ewa M Jonkers, Jos Berns, Anton
spellingShingle	Huijbers, Ivo J Bin Ali, Rahmen Pritchard, Colin Cozijnsen, Miranda Kwon, Min-Chul Proost, Natalie Song, Ji-Ying Vries, Hilda Badhai, Jitendra Sutherland, Kate Krimpenfort, Paul Michalak, Ewa M Jonkers, Jos Berns, Anton Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
author_facet	Huijbers, Ivo J Bin Ali, Rahmen Pritchard, Colin Cozijnsen, Miranda Kwon, Min-Chul Proost, Natalie Song, Ji-Ying Vries, Hilda Badhai, Jitendra Sutherland, Kate Krimpenfort, Paul Michalak, Ewa M Jonkers, Jos Berns, Anton
author_sort	Huijbers, Ivo J
title	Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
title_short	Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
title_full	Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
title_fullStr	Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
title_full_unstemmed	Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
title_sort	rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells
description	Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.
publisher	Blackwell Publishing Ltd
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927956/
_version_	1612059613218209792

Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells

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