Genetically engineered mouse models of melanoma

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.

[1]  R. M. Thomas,et al.  Concepts in Cancer Modeling: A Brief History. , 2016, Cancer research.

[2]  K. Brown,et al.  The genomic landscape of cutaneous melanoma , 2016, Pigment cell & melanoma research.

[3]  M. McMahon,et al.  AKT1 Activation Promotes Development of Melanoma Metastases. , 2015, Cell reports.

[4]  Chi-Ping Day,et al.  Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges , 2015, Cell.

[5]  J. Huang,et al.  Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice. , 2015, Cancer research.

[6]  Steven J. M. Jones,et al.  Genomic Classification of Cutaneous Melanoma , 2015, Cell.

[7]  I. Jackson,et al.  Maintenance of distinct melanocyte populations in the interfollicular epidermis , 2015, Pigment cell & melanoma research.

[8]  Michael B. Mann,et al.  Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma , 2015, Nature Genetics.

[9]  N. Bardeesy,et al.  mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. , 2015, Cancer cell.

[10]  David B. Darr,et al.  Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. , 2014, Cancer discovery.

[11]  Janan T. Eppig,et al.  Mouse Tumor Biology (MTB): a database of mouse models for human cancer , 2014, Nucleic Acids Res..

[12]  L. Chodosh,et al.  Tetracycline-regulated mouse models of cancer. , 2014, Cold Spring Harbor protocols.

[13]  K. Flaherty,et al.  The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα. , 2014, Cancer discovery.

[14]  A. Bosserhoff,et al.  Tg(Grm1) transgenic mice: a murine model that mimics spontaneous uveal melanoma in humans? , 2014, Experimental eye research.

[15]  Atsushi Miyawaki,et al.  Fucci2a: A bicistronic cell cycle reporter that allows Cre mediated tissue specific expression in mice , 2014, Cell cycle.

[16]  G. Merlino,et al.  Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. , 2014, Cancer cell.

[17]  N. Dhomen,et al.  Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53 , 2014, Nature.

[18]  D. Schadendorf,et al.  Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma , 2014, Nature.

[19]  B. Bastian The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. , 2014, Annual review of pathology.

[20]  R. Sullivan,et al.  Resistance to BRAF-targeted therapy in melanoma. , 2013, European journal of cancer.

[21]  P. Wesseling,et al.  Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes. , 2013, Cancer discovery.

[22]  Gerald C. Chu,et al.  Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma , 2012, Nature Medicine.

[23]  Jane Fridlyand,et al.  Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors , 2012, Nature.

[24]  T. Golub,et al.  Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion , 2012, Nature.

[25]  C. Perou,et al.  LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma. , 2012, Cancer cell.

[26]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[27]  M. Tucker,et al.  Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment , 2012, Nature Communications.

[28]  D. Rimm,et al.  β-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. , 2011, Cancer cell.

[29]  P. Pandolfi,et al.  In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma , 2011, Cell.

[30]  J. Landsberg,et al.  Neonatal UVB exposure accelerates melanoma growth and enhances distant metastases in Hgf‐Cdk4R24C C57BL/6 mice , 2011, International journal of cancer.

[31]  L. Sommer Generation of melanocytes from neural crest cells , 2011, Pigment cell & melanoma research.

[32]  F. Beermann,et al.  A mart‐1::Cre transgenic line induces recombination in melanocytes and retinal pigment epithelium , 2011, Genesis.

[33]  G. Merlino,et al.  A genetically engineered mouse model with inducible GFP expression in melanocytes , 2011, Pigment cell & melanoma research.

[34]  S. Holmen,et al.  Animal models of melanoma: a somatic cell gene delivery mouse model allows rapid evaluation of genes implicated in human melanoma , 2011, Chinese journal of cancer.

[35]  Sean Davis,et al.  Interferon-γ links ultraviolet radiation to melanomagenesis in mice. , 2011, Nature.

[36]  J. O'Brien,et al.  Mutations in GNA11 in uveal melanoma. , 2010, The New England journal of medicine.

[37]  S. Holmen,et al.  Targeted delivery of NRASQ61R and Cre‐recombinase to post‐natal melanocytes induces melanoma in Ink4a/Arflox/lox mice , 2010, Pigment cell & melanoma research.

[38]  J. Bishop,et al.  A new transgenic mouse line for tetracycline inducible transgene expression in mature melanocytes and the melanocyte stem cells using the Dopachrome tautomerase promoter , 2010, Transgenic Research.

[39]  N. Dhomen,et al.  Inducible expression of V600EBraf using tyrosinase‐driven Cre recombinase results in embryonic lethality , 2010, Pigment cell & melanoma research.

[40]  U. Suter,et al.  Schwann Cell Precursors from Nerve Innervation Are a Cellular Origin of Melanocytes in Skin , 2009, Cell.

[41]  Shosuke Ito,et al.  Current challenges in understanding melanogenesis: bridging chemistry, biological control, morphology, and function , 2009, Pigment cell & melanoma research.

[42]  Jimmy Lin,et al.  Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4 , 2009, Nature Genetics.

[43]  Anastassia Stoykova,et al.  Pax6 dosage requirements in iris and ciliary body differentiation. , 2009, Developmental biology.

[44]  N. Ibrahim,et al.  Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice , 2009, Oncogene.

[45]  J. Reis-Filho,et al.  Oncogenic Braf induces melanocyte senescence and melanoma in mice. , 2009, Cancer cell.

[46]  R. DePinho,et al.  BRafV600E cooperates with Pten silencing to elicit metastatic melanoma , 2009, Nature Genetics.

[47]  K. R. Fitch,et al.  Melanocyte‐lineage expression of Cre recombinase using Mitf regulatory elements , 2007, Pigment cell & melanoma research.

[48]  David A. Tuveson,et al.  Maximizing mouse cancer models , 2007, Nature Reviews Cancer.

[49]  Jin Namkoong,et al.  Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma. , 2007, Cancer research.

[50]  D. Fisher,et al.  Melanocyte biology and skin pigmentation , 2007, Nature.

[51]  M. Barbacid,et al.  Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. , 2006, The American journal of pathology.

[52]  L. Chin,et al.  Characterization of melanocyte‐specific inducible Cre recombinase transgenic mice , 2006, Genesis.

[53]  L. Larue,et al.  Spatiotemporal gene control by the Cre‐ERT2 system in melanocytes , 2006, Genesis.

[54]  A. Trumpp,et al.  Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. , 2005, Cancer research.

[55]  J. Epstein,et al.  Pax3 functions at a nodal point in melanocyte stem cell differentiation , 2005, Nature.

[56]  Glenn Merlino,et al.  Ultraviolet B but not Ultraviolet A Radiation Initiates Melanoma , 2004, Cancer Research.

[57]  E. Fuchs,et al.  Defining the Epithelial Stem Cell Niche in Skin , 2004, Science.

[58]  L. Chin,et al.  Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo , 2003, Oncogene.

[59]  J. Reis-Filho,et al.  Expression of c-met Tyrosine Kinase Receptor Is Biologically and Prognostically Relevant for Primary Cutaneous Malignant Melanomas , 2003, Oncology.

[60]  B. Gilchrest,et al.  Fate of melanocytes during development of the hair follicle pigmentary unit. , 2003, The journal of investigative dermatology. Symposium proceedings.

[61]  F. Haluska,et al.  PTEN signaling pathways in melanoma , 2003, Oncogene.

[62]  E. Dupin,et al.  Development of melanocyte precursors from the vertebrate neural crest , 2003, Oncogene.

[63]  P. Meltzer,et al.  Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia , 2003, Nature Genetics.

[64]  R. DePinho,et al.  Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. , 2002, Cancer research.

[65]  P. Chambon,et al.  Site-specific somatic mutagenesis in the retinal pigment epithelium. , 2002, Investigative ophthalmology & visual science.

[66]  M. Barbacid,et al.  Invasive melanoma in Cdk4-targeted mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[67]  M. Lewandoski Conditional control of gene expression in the mouse , 2001, Nature Reviews Genetics.

[68]  P. Duray,et al.  Neonatal sunburn and melanoma in mice , 2001, Nature.

[69]  L. Chin,et al.  Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas , 2001, Molecular and Cellular Biology.

[70]  L. Hou,et al.  Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. , 2000, Development.

[71]  D. Finkelstein,et al.  Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma. , 2000, Archives of Dermatology.

[72]  W. Pavan,et al.  Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[73]  G. Merlino,et al.  Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice. , 2000, Cancer research.

[74]  Andras Nagy,et al.  Cre recombinase: The universal reagent for genome tailoring , 2000, Genesis.

[75]  P. Guldberg,et al.  Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. , 2000, The Journal of investigative dermatology.

[76]  P Chambon,et al.  Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. , 1999, Nucleic acids research.

[77]  F. Beermann The tyrosinase related protein-1 (Tyrp1) promoter in transgenic experiments: targeted expression to the retinal pigment epithelium. , 1999, Cellular and molecular biology.

[78]  R. Nagle,et al.  Induction of melanoma in TPras transgenic mice. , 1999, Carcinogenesis.

[79]  F. Beermann,et al.  Ectopic expression of ret results in microphthalmia and tumors in the retinal pigment epithelium , 1999, International journal of cancer.

[80]  R. Sharp,et al.  c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. , 1998, Cancer research.

[81]  T. Mak,et al.  High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice , 1998, Current Biology.

[82]  Wei Liu,et al.  Transgenic mouse model for skin malignant melanoma , 1998, Oncogene.

[83]  Kevin Ryan,et al.  The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2 , 1998, The EMBO journal.

[84]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[85]  I. Jackson,et al.  Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo. , 1997, Developmental biology.

[86]  L. Chin,et al.  Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. , 1997, Genes & development.

[87]  P. Guldberg,et al.  Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. , 1997, Cancer research.

[88]  R. Sharp,et al.  Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[89]  P Chambon,et al.  Ligand-activated site-specific recombination in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[90]  L. Chin,et al.  Role of the INK4a Locus in Tumor Suppression and Cell Mortality , 1996, Cell.

[91]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.

[92]  B. Dynlacht,et al.  Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition , 1995, Nature.

[93]  A. Balmain,et al.  Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 HA‐ras gene regulated by a mouse tyrosinase promoter , 1995, Molecular carcinogenesis.

[94]  W. Clark,et al.  Germline p16 mutations in familial melanoma , 1994, Nature Genetics.

[95]  W. Silvers,et al.  Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice. , 1994, Cancer research.

[96]  S. Cory,et al.  Transgenic models of tumor development. , 1991, Science.

[97]  P. Haninec,et al.  Tyrosinase protein is expressed also in some neural crest derived cells which are not melanocytes. , 1988, Pigment cell research.

[98]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[99]  Jochen K. Lennerz,et al.  An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair / fair skin background , 2012 .

[100]  G. Barsh,et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi , 2010 .

[101]  M. McMahon,et al.  Characterization of melanoma cells capable of propagating tumors from a single cell. , 2010, Cancer research.

[102]  T. Tsuzuki,et al.  A novel mouse model for de novo Melanoma. , 2010, Cancer research.

[103]  B. Sauer,et al.  Conditional gene knockout using Cre recombinase. , 2001, Molecular biotechnology.

[104]  N. Hayward,et al.  Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma , 1996, Nature Genetics.

[105]  M. Bradl,et al.  Malignant melanoma in transgenic mice. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[106]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.