Molecular Pathogenesis of Rodent Neoplasia

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

The primary goals of the project Molecular Pathogenesis of Rodent Neoplasia are to understand the mechanisms of chemical carcinogenesis, evaluate the translational relevance of the rodent data to human health and discover biomarkers that can predict an exposure or disease using tissues from short term rodent studies or in vitro studies. One of the goals of this project is to understand the molecular alterations that are causally associated with the phenotype, i.e. lesions. So, the typical starting point is the tumor resulting from chronic (2 years) chemical exposure. As the NTP is focusing more on a streamlined translational toxicology pipeline that aims to bridge the toxicological or carcinogenic mechanisms at various levels of biological complexity, this project aims to understand the mechanisms in the rodent species, which have a higher level of biological complexity. The ultimate goal is to link the mechanistic knowledge obtained from rodent models to the corresponding human disease. Some of the examples of these studies done by our group include understanding the epigenetic alterations such as methylation profiles and miRNA profiles as well as somatic mutations in spontaneous and chemical-induced mouse hepatocellular carcinomas resulting from exposure to Ginkgo biloba extract. These publications are indicated in the bibliography. Other projects in progress include a multi-omics next-generation sequencing approach to examine the whole exome, transcriptome, and small RNA alterations in mouse hepatocellular tumors resulting from chronic exposure to 4 genotoxic and 6 non-genotoxic chemicals. Furthermore, in collaboration with external partners such as Dr. Dave Adams from Wellcome Sanger Institute and Dr. Allan Balmain from the University of California, San Francisco, we have examined the whole genomes of hepatocellular tumors and alveolar bronchiolar carcinomas from mice exposed to various known or suspected human carcinogens. These data have recently been accepted in the Nature Genetics journal. Our current efforts are to expand these approaches to examine other rodent tumors from the archives at the NTP and at the Ramazzini Institute. In addition, we are focusing on identifying driver gene mutations that can be used to develop a cancer gene panel to screen tissues from short-term animal studies and predict a carcinogenic response. If successful, this will obviate the need to run the 2-year rodent cancer bioassays in a routine manner for most suspected carcinogenic chemicals.