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Keywords:

  • cancer;
  • chimeras;
  • embryonic stem cells;
  • mouse models;
  • MycL1

Abstract

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.

Synopsis

Thumbnail image of graphical abstract

The GEMM-ESC approach describes and validates an improved method for generating mouse cancer models directly from embryonic stem cells. This technology speeds up the generation/modification of mouse models, while minimizing cost and breeding efforts.

  • ESCs cultured in 2i medium show improved pluripotency and display equal genomic stability as ESCs cultured under classic conditions.
  • Chimeric mice generated from GEMM-ESCs are equally susceptible to tumors as compared to the parental strain, provided the chimeras display coat color contribution upwards of 70%.
  • Experimental cohorts are generated on-demand in less than 4 months without the need for any breeding.
  • Controlled single copy integration of a transgene in the Col1a1 locus allows for robust reporter and oncogene expression in a mouse model for small cell lung cancer.
  • Archived ESCs with complex genetic traits can serve as an important resource for the generation of new mouse models of cancer or for the validation of candidate cancer genes.