A C. elegans model for studying blocks to EGFR signal transduction in quiescent cells

Reversible exit from the cell cycle, or cellular quiescence, is a feature of both normal and cancer stem cells. Quiescent adult stem cells are critical for tissue maintenance and stress response. In contrast, quiescent cancer stem cells are a cause of tumor recurrence, as these cells are able to resist chemotherapy that targets actively dividing cells.Therefore, understanding basic features of stem cell biology and identifying novel therapeutic targets for quiescent cancer cells are of great clinical interest. Caenorhabditis elegans has proven to be a powerful model to investigate pathways involved in the maintenance of long term arrest. In unfavorable conditions, C. elegans larvae enter a long-lived state, known as dauer, in which cells remain quiescent and multipotent for months at a time?several times the normal lifespan of the animal. Entry into the dauer state is associated with blocks to Epidermal Growth Factor Receptor (EGFR) signal transduction. The C. elegans Vulval Precursor Cells (VPCs) have long been used to study mechanisms regulating cell fate decisions and this tractable system is subject to dauer induced arrest. This project aims to use VPCs to identify fundamental mechanisms by which conserved signaling pathways block the EGFR pathway in quiescent and multipotent cells by 1) determining the level at which EGFR signaling is regulated in dauer 2) removing putative negative regulators in order to induce VPC division and differentiation during dauer 3) using in vivo fluorescent kinase reporters to determine if stereotyped signaling dynamics characterize dauer arrest. These aims will identify crosstalk between signaling cascades and provide a model for the regulation mechanism associated with long term maintenance of quiescence.