Non-germline genetically engineered mouse models for translational cancer research

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.

Figure 1. Conditional genetically engineered mouse models (GEMMs)

a | Activating Cre in a tissue-specific manner, by either viral delivery or Cre-oestrogen response element (ERE)-mediated tamoxifen administration. Examples are shown for lung cancer and ovarian cancer, and melanoma. b | Tetracycline (Tet)-mediated transgene inactivation or activation by doxycycline administration or withdrawal using the Tet-On or Tet-Off systems. Examples are shown for liver cancer and melanoma. fl, flox; lsl, lox-STOP-lox; rtTA, reverse transactivator; tTA, transactivator.

Figure 2. Chimeric model generation

a | Genetically modified embryonic stem cells are transduced ex vivo with conditional oncogenic transgenes, injected into blastocysts and implanted into pseudopregnant mice to generate chimeras. b | By activating the respective transgenes in a tissue-specific manner, multiple tumour types can be induced in these chimeras in the context of normal stromal tissue derived from the wild-type blastocysts. Image is modified, with permission, from Nature Biotechnology REF. © (2010) Macmillan Publishers Ltd. All rights reserved. DKO, double knockout; EGFR, epidermal growth factor receptor; Luc, luciferase; rtTA, reverse transactivator; Tet, tetracycline.

Figure 3. Human in mouse transplantation models

Pluripotent human stem cells are grown ex vivo on feeder cells and transduced with the oncogenic elements of interest. Without long culture times, the cells are injected into orthotopic sites on the mice with or without humanized stromal cells. Here, the tumour types of interest will develop from human cells within the context of the relevant mouse or human normal stroma.