Open AccessRapid target gene validation in complex cancer mouse models using re‐derived embryonic stem cells
Author(s) -
Huijbers Ivo J,
Bin Ali Rahmen,
Pritchard Colin,
Cozijnsen Miranda,
Kwon MinChul,
Proost Natalie,
Song JiYing,
Vries Hilda,
Badhai Jitendra,
Sutherland Kate,
Krimpenfort Paul,
Michalak Ewa M,
Jonkers Jos,
Berns Anton
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303297
Subject(s) - embryonic stem cell , computational biology , cre recombinase , cancer , lung cancer , biology , cancer stem cell , cancer research , gene , computer science , transgene , genetically modified mouse , medicine , genetics , pathology
Human cancers modeled in Genetically Engineered Mouse Models ( GEMM s) 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 GEMM s; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells ( ESC s) from established GEMM s, (ii) the routine introduction of transgenes of choice in these GEMM ‐ ESC s by F lp 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.