title: C. elegans as a model organism for in vivo screening in cancer: effects of human c-Met in lung cancer affect C. elegans vulva phenotypes.
abstract: Cancers typically harbour several mutant forms of key cellular genes that contribute to its complex phenotype. Our lab has previously identified gain-of-function mutations in some of the receptor tyrosine kinases such as c-Met in lung cancer. In order to investigate the mutant gene in the context of a whole organism, the current choice of in vivo model is limited to the mouse. To rapidly screen the functional aspects of mutant forms of c-Met detected in lung cancer, we used the nematode C. elegans as the model organism. Transgenic worms were generated that harbour wild type or the frequently seen mutant forms of c-Met in lung cancer (c-MetR988C and c-MetT1010I). Expression of the mutant human c-Met forms in C. elegans consistently resulted in significantly low fecundity and abnormal vulval development characterized by hyperplasia. Interestingly, exposure of c-Met mutant transgenic worms to nicotine resulted in enhanced abnormal vulval development, fecundity and locomotion. Our studies provide first evidence that human c-Met mutations can be studied in C. elegans, and that carcinogens can enhance mutant c-Met function expressed in C. elegans transgenic animals. We therefore propose the use of C. elegans as a model to rapidly assess the role of cancer specific gene mutations in the context of a whole organism.
authors.affiliation: Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
authors.forename: Shahid S
authors.initials: SS
authors.lastname: Siddiqui
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Loganathan
authors.forename: Soundararajan
authors.initials: S
authors.lastname: Krishnaswamy
authors.forename: Leonardo
authors.initials: L
authors.lastname: Faoro
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Jagadeeswaran
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009154:Mutation; D009538:Nicotine / Q000737:chemistry; D010641:Phenotype; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics*; D034622:RNA Interference; D014844:Vulva / Q000187:drug effects* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D009538:Nicotine; D019859:Proto-Oncogene Proteins c-met