Non-germline genetically engineered mouse models for translational cancer research

Key Points

  • Genetically engineered mouse models (GEMMs) have been invaluable in advancing our knowledge of tumour biology. However, accelerated cancer gene discovery through large-scale cancer genomics and an increasing desire to use GEMMs for preclinical therapeutic studies have strained the capacity of germline GEMMs.

  • Non-germline genetic engineering approaches allow for accelerated and flexible genetic manipulation of models.

  • Chimeric models develop tumours in the context of normal stroma, with reduced timelines and mouse housing cost.

  • Transplantation models allow flexible and speedy manipulation of tissue stem and/or progenitor cells with multiple genetic tools (such as knock out, transgenes and RNA interference).

  • Human donor tissue models (or human in mouse models) allow the de novo development of primary human tumours in mouse stroma by manipulating primary human cells.

  • Therapeutic studies in vivo benefit from the wealth of complex GEMM and non-GEMM models to guide drug discovery.

Abstract

Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models.

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Figure 1: Conditional genetically engineered mouse models (GEMMs).
Figure 2: Chimeric model generation.
Figure 3: Human in mouse transplantation models.

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Correspondence to Lynda Chin.

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Competing interests

J. H. is an employee of AVEO Pharmaceuticals.

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DATABASES

National Cancer Institute Drug Dictionary 

AV-412

bevacizumab

BEZ235

cyclophosphamide

doxycycline

erlotinib

perifosine

tetracycline

trastuzumab

OMIM

Li–Fraumeni syndrome

Pathway Interaction Database 

p53

FURTHER INFORMATION

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Glossary

Germline model

Mouse model that carries genetic modifications in its germline and which is maintained through breeding.

Inducible model

Mouse model that activates the expression of a transgene through a transactivator transgene that is, tTA or rtTA.

Non-germline GEMM (nGEMM)

Mouse model that carries genetic modifications in some of its somatic cells but not in the germline cells. Each model has to be individually generated through, for example, transplantation and injection.

Mosaic model

Germline model that acquires modifications of the germline genetic modification in some of its somatic cells.

Conditional GEMM

Model that acquires an activation or inactivation of the original genetic modification in somatic cells through the temporal or spatial expression of a modifier such as Cre.

Chimeric model

Mouse model that has been generated by ESC manipulation followed by the injection of these cells into a pre-implantation embryo. The resulting chimeric animal is the model animal.

Transplantation model

Mouse model in which part of a tissue is modified by transplanting tissue stem cells that carry genetic modifications.

Human in mouse (HIM) model

Transplantation model in which the transplanted cells are human tissue stem cells.

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Heyer, J., Kwong, L., Lowe, S. et al. Non-germline genetically engineered mouse models for translational cancer research. Nat Rev Cancer 10, 470–480 (2010). https://doi.org/10.1038/nrc2877

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