Journal Article

“Glowing Head” Mice: A Genetic Tool Enabling Reliable Preclinical Image-Based Evaluation of Cancers in Immunocompetent Allografts

Ohler, Zoe Weaver, Feigenbaum, Lionel, Hollingshead, Melinda, Merlino, Glenn, Graff-Cherry, Cari, Bonomi, Carrie, El Meskini, Rajaa, Carter, John, Martin, Philip, Van Dyke, Terry, Day, Chi-Ping, Tüting, Thomas

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenoviruses / Allografts / Animal models / Animal sciences / Animals / Antigenicity / Antigens / Antineoplastic Agents, Phytogenic - therapeutic use / Binding sites / Biology and Life Sciences / Biomedical research / Cancer / Cell Line, Tumor / Chemotherapy / Disease Models, Animal / Drug Evaluation, Preclinical / Evaluation / Female / Gems / Genes, Reporter / Genetic engineering / Growth hormone / Human behavior / Immune response / Immunocompetence / Immunocompromised Host / Immunomodulation / Kaplan-Meier Estimate / Kinetics / Laboratory animals / Luciferases - genetics / Luciferases - metabolism / Lung Neoplasms - drug therapy / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Male / Medical research / Medicine and Health Sciences / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Mice, SCID / Mice, Transgenic / Paclitaxel - therapeutic use / Pharmaceutical industry / Pituitary (anterior) / Pituitary gland / Pituitary Gland - metabolism / Proteins / Rodents / Science programs / Studies / Transplantation / Transplantation, Homologous / Tumor cells / Tumors / Xenografts / Zoology