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Joshua Clair Snyder, PhD

Assistant Professor of Surgery
Assistant Professor of Cell Biology
Office: Msrbi Rm 475A, Durham, NC 27710
Campus Mail: DUMC Box 3287 Med Ctr, Durham, NC 27710

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

Publications

Jacobsen, Jacob P. R., Adrianna Oh, Rachel Bangle, Wendy L. Roberts, Elizabeth L. Royer, Nathan Modesto, Sonora A. Windermere, et al. “Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept..” Neuropsychopharmacology 44, no. 12 (November 2019): 2082–90. https://doi.org/10.1038/s41386-019-0400-1.

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Crosby, Erika J., William Gwin, Kimberly Blackwell, Paul K. Marcom, Serena Chang, Holden T. Maecker, Gloria Broadwater, et al. “Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study..” Clin Cancer Res 25, no. 9 (May 1, 2019): 2725–36. https://doi.org/10.1158/1078-0432.CCR-18-3102.

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Crosby, E. J., W. R. Gwin, S. Chang, H. T. Maecker, V. Lubkov, J. C. Snyder, G. Broadwater, et al. “Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients.” In Poster Session Abstracts. American Association for Cancer Research, 2019. https://doi.org/10.1158/1538-7445.sabcs18-p2-09-16.

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Mackie, Duncan I., Fuad Al Mutairi, Reema B. Davis, Daniel O. Kechele, Natalie R. Nielsen, Joshua C. Snyder, Marc G. Caron, et al. “hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia..” J Exp Med 215, no. 9 (September 3, 2018): 2339–53. https://doi.org/10.1084/jem.20180528.

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Snyder, Joshua C., Lauren K. Rochelle, Caroline Ray, Thomas F. Pack, Cheryl B. Bock, Veronica Lubkov, H Kim Lyerly, Alan S. Waggoner, Larry S. Barak, and Marc G. Caron. “Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled receptor-5 diminishes cell fitness..” J Biol Chem 292, no. 17 (April 28, 2017): 7208–22. https://doi.org/10.1074/jbc.M116.756635.

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Urs, Nikhil M., Steven M. Gee, Thomas F. Pack, John D. McCorvy, Tama Evron, Joshua C. Snyder, Xiaobao Yang, et al. “Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties..” Proc Natl Acad Sci U S A 113, no. 50 (December 13, 2016): E8178–86. https://doi.org/10.1073/pnas.1614347113.

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Urs, Nikhil, Steven Gee, Thomas F. Pack, John McCorvy, Tama Evron, Joshua C. Snyder, Ramona Rodriguiz, et al. “A Unique Dual Cortico-Striatal Action of a Beta-Arrestin Biased Dopamine D2 Receptor Ligand.” In Biological Psychiatry, 79:408S-408S. ELSEVIER SCIENCE INC, 2016.

Scholars@Duke

Snyder, Joshua C., Thomas F. Pack, Lauren K. Rochelle, Subhasish K. Chakraborty, Ming Zhang, Andrew W. Eaton, Yushi Bai, et al. “A rapid and affordable screening platform for membrane protein trafficking..” Bmc Biol 13 (December 17, 2015). https://doi.org/10.1186/s12915-015-0216-3.

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Snyder, Joshua C., Lauren K. Rochelle, Sébastien Marion, H Kim Lyerly, Larry S. Barak, and Marc G. Caron. “Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions..” J Cell Sci 128, no. 6 (March 15, 2015): 1230–40. https://doi.org/10.1242/jcs.166322.

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