My research objective is to translate basic science discoveries into treatments and cures for cancer. My work primarily focuses on G protein-coupled receptors (GPCR)s as a primary target in cancer. GPCRs are the largest family of receptors encoded by the genome, tightly control cell signaling, and regulate physiology in a diversity of tissues. As such, they are historically among the best targets for small molecule therapy in the clinic. The leucine-rich G protein-coupled receptor-5 (Lgr5) is particularly interesting since it is expressed in stem and cancer stem cells in a myriad of tissues. However, the function of Lgr5 is still largely unknown. Currently, my work utilizes cutting-edge multidisciplinary approaches to tackle this important challenge. This includes genetic engineering of fluorescently labelled mice, high-content confocal microscopy and cell behavior modeling, organoid culturing and genome editing, and fluorescent based approaches for high-throughput screening of receptor trafficking.
Using these approaches, we have made several important discoveries regarding Lgr5 that are facilitating future studies. We found that Lgr5 drives the formation of very long cellular protrusions that serve as scaffolds for cell signaling. We are continuing to investigate the mechanistic importance of this finding using mouse models and intestinal organoid cultures to view this process in living mice. Another key observation was our discovery that Lgr5 internalization and trafficking are critical for regulating its function. Current work is now working toward a more mechanistic characterization of Lgr5 trafficking using fluorescent sensors that are capable of quantitatively assessing this dynamic process. We are also actively screening small molecule libraries in an effort to discover potential agonists/antagonists of Lgr5 that may be useful clinically in cancer treatment or in tissue regeneration. Lastly, we are continuing to develop additional technologies for directing gene expression in vivo in order to study the structure/function of tumor driver genes with greater sensitivity and more cellular resolution. Our strategy enables the simultaneous expression of multiple driver genes in vivo along with the ability to monitor their effects on cell fate and behavior. Importantly, many of the tools that we have developed are broadly applicable to other receptors and candidate tumor driver genes for which we are open for collaboration.
We are currently accepting applications for a post doctoral research fellow that will work on projects related to Lgr5 drug discovery and the cell fitness mechanisms driving tumorigenesis. Qualified applicants can apply here: https://careers.nationalpostdoc.org/job/postdoctoral-fellow-cell-biology-and-pharmacologycancer-biology/40147366/.
Education and Training
- Ph.D., University of Pittsburgh School of Medicine, 2009
In the News
- Training Program in Developmental and Stem Cell Biology
- Establishing the molecular and cellular mechanisms of Lgr5 signaling for controlling cancer stem cell behavior
- Only the strong survive: Microenvironmental and genetic determinants of organotropism
- A Cancer Rainbow Mouse for Simultaneous Assessment of Multiple Oncogenes
- Beta-catenin modulates dopamine dependent signal transduction and behavior.