title: "Glowing head" mice: a genetic tool enabling reliable preclinical image-based evaluation of cancers in immunocompetent allografts.
abstract: Preclinical therapeutic assessment currently relies on the growth response of established human cell lines xenografted into immunocompromised mice, a strategy that is generally not predictive of clinical outcomes. Immunocompetent genetically engineered mouse (GEM)-derived tumor allograft models offer highly tractable preclinical alternatives and facilitate analysis of clinically promising immunomodulatory agents. Imageable reporters are essential for accurately tracking tumor growth and response, particularly for metastases. Unfortunately, reporters such as luciferase and GFP are foreign antigens in immunocompetent mice, potentially hindering tumor growth and confounding therapeutic responses. Here we assessed the value of reporter-tolerized GEMs as allograft recipients by targeting minimal expression of a luciferase-GFP fusion reporter to the anterior pituitary gland (dubbed the "Glowing Head" or GH mouse). The luciferase-GFP reporter expressed in tumor cells induced adverse immune responses in wildtype mouse, but not in GH mouse, as transplantation hosts. The antigenicity of optical reporters resulted in a decrease in both the growth and metastatic potential of the labeled tumor in wildtype mice as compared to the GH mice. Moreover, reporter expression can also alter the tumor response to chemotherapy or targeted therapy in a context-dependent manner. Thus the GH mice and experimental approaches vetted herein provide concept validation and a strategy for effective, reproducible preclinical evaluation of growth and response kinetics for traceable tumors.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Day
authors.affiliation: In Vivo Evaluation, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Carter
authors.affiliation: Center for Advanced Preclinical Research of Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Weaver Ohler
authors.affiliation: In Vivo Evaluation, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Bonomi
authors.affiliation: Center for Advanced Preclinical Research of Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Meskini
authors.affiliation: Center for Advanced Preclinical Research of Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Martin
authors.affiliation: Laboratory Animal Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Cari
authors.initials: C
authors.lastname: Graff-Cherry
authors.affiliation: Laboratory Animal Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Center for Advanced Preclinical Research of The Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D017930:Genes, Reporter; D016867:Immunocompromised Host; D053208:Kaplan-Meier Estimate; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D017239:Paclitaxel / Q000627:therapeutic use; D010902:Pituitary Gland / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008156:Luciferases; D017239:Paclitaxel