Genetically engineered mouse models of melanoma

Abstract

Melanoma is a complex disease that exhibits highly heterogeneous etiological, histopathological, and genetic features, as well as therapeutic responses. Genetically engineered mouse (GEM) models provide powerful tools to unravel the molecular mechanisms critical for melanoma development and drug resistance. Here, we expound briefly the basis of the mouse modeling design, the available technology for genetic engineering, and the aspects influencing the use of GEMs to model melanoma. Furthermore, we describe in detail the currently available GEM models of melanoma. Cancer 2017;123:2089-103. © 2017 American Cancer Society.

Keywords: carcinogen; genetically engineered mice; melanoma; mouse models; ultraviolet (UV) radiation.

Fig. 1

Timeline of expression of melanocyte-specific genes during mouse embryogenesis. The promoters of these genes are good candidates to be used to drive expression of transgenes in melanocyte-specific manner in mouse models of melanoma and melanocyte biology. The black bar depicts embryonic (E) developmental days of gestation (from E9.5 to E18.5). Mitf, Microphthalmia Associated Transcription Factor; Dct, Dopachrome tautomerase; Mlana, Melanoma antigen recognized by T-cells; Pmel, Premelanosome protein; Trp1, Tyrosinase-related protein 1; Tyr, Tyrosinase. (Adapted from ref. 33).

Fig. 2

The iDct-GFP mouse model. This tet-inducible (Tet-On) model expresses green fluorescent protein (GFP) in the melanoblast/melanocyte compartment during embryonic stages (a) and adult skin (b). In this mouse, the rtTA is driven by the Dct promoter, and GFP is under the control of TRE promoter. The expression of GFP is activated in the embryos by feeding the pregnant dam with doxycycline-fortified diet, and in adult mice by a single doxycycline injection 24h prior to imaging. (a) At embryonic day 11.5 (E11.5) time point, the GFP is expressed in the neural crest (NC), retinal pigment epithelium (RPE), and telencephalon (T) of an iDct-GFP embryo. (b) An iDct-GFP; HGF/SF-Tg mouse that was UVB-irradiated at neonatal day 3.5 and imaged via Xenogen IVIS system at 4 weeks of age. The enhanced number of epidermal melanocytes and nevi can be readily visualized on shaven dorsal skin, ears, eyes, paws, and tail (see text and ref. for details).

Fig. 3

The main pathways altered in GEMMs of cutaneous melanoma. The principal oncogenic modifications introduced in mouse models of melanoma involve the activation of RAS/RAF/MEK/ERK and phosphoinositide-3 kinase (PI3K) pathways, the most frequently altered pathways in human melanomas. Stimulation of receptor tyrosine kinases (RTK) by binding of growth factors (GF) leads to the activation of these pathways resulting in induction of proliferation and/or migration and invasion. Alternatively, RAS/RAF/MEK/ERK pathway can be induced by direct activation of RAF proteins by G protein-coupled receptors (GPCR). Deletion of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) can also indirectly activate PI3K pathway. In addition, cell cycle progression can be induced by the oncogenic activation of cyclin-dependent kinase 4 (CDK4) or the inactivation of the tumor suppressors cyclin-dependent kinase inhibitor 2A (CDKN2A) or p53. The specific allelic modifications available in mouse models of melanoma are highlighted in red (also see Table 1).