Crislyn D'Souza-Schorey Morris Pollard Professor; Department Chair
The most unfavorable events during the early stages of cancer progression are tightly linked to alterations in signaling cascades that control cell adhesion and invasion. Research in our laboratory focuses on a signaling axis that facilitates these changes and appears to be deregulated in several human cancers. We work at the intersection of two exciting disciplines in the life sciences, cell biology and oncology. The acquisition of the invasive phenotype—when cells disrupt normal cell-cell contacts and acquire phenotypic alterations that permit invasion through the surrounding tissue—is the focus of the laboratory’s research. With this framework, we seek to determine the impact of specific molecular alterations in cancer initiation and progression, with the ultimate goal of extending these findings to the development of new diagnostic and therapeutic platforms.
Our efforts have stemmed from a long-standing interest in understanding the cellular roles of the small GTP-binding protein, ARF6. We documented that ARF6-regulated signaling and its effect on membrane trafficking can directly impact the adhesive and migratory properties of normal and tumor cells. Collectively, this work has revealed mechanisms of disease pathogenesis as well as new targets for drug action. Current investigations are targeted at understanding the cellular basis of epithelial glandular disruption and tumor cell invasion. In these contexts, we are investigating the mechanisms that govern the formation of tumor-derived microvesicles and their paracrine properties. We continue to characterize these invasive structures and investigate the mechanisms by which they promote tumor cell migration and dissemination across diverse microenvironments. Through these investigations, we seek to uncover the molecular basis of pathological phenotypes observed in biopsies of patients with localized and invasive ductal carcinomas. Our research pursuits employ cellular, organotypic and animal model systems, coupled with the interrogation of clinical samples.
- Department Chair, Biological Sciences, University of Notre Dame, IN 2014-Present
- Professor, Department of Biological Sciences, University of Notre Dame, IN 2011-Present
- Associate Professor, Department of Biological Sciences, University of Notre Dame, IN 2004-2011
- Assistant Professor, Department of Biological Sciences, University of Notre Dame, IN 1998-2004
- Research Assistant Professor, Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 1997-1998
- Postdoctoral Fellow, Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 1993-1996
- Ph.D. University of Texas Health Science Center at San Antonio, TX 1992
- Sedgwick AE, D'Souza-Schorey C. (2016) Wnt Signaling in Cell Motility and Invasion: Drawing Parallels between Development and Cancer. Cancers. 8(9). pii: E80. doi: 10.3390/cancers8090080.
- Clancy JW, Sedgwick A, Rosse C, Muralidharan-Chari V, Raposo G, Method M, Chavrier P, D'Souza-Schorey C. (2015) Regulated delivery of molecular cargo to invasive tumour-derived microvesicles. Nature Commun. 6: 6919-6930.
- Sedgwick AE, Clancy JW, Olivia Balmert M, D'Souza-Schorey C. (2015) Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion. Scientific Reports. 5:14748. doi: 10.1038/srep14748.
- Pellon-Cardenas O, Clancy J, Uwimpuhwe H, D'Souza-Schorey C. (2013) ARF6-Regulated Endocytosis of Growth Factor Receptors Links Cadherin-Based Adhesion to Canonical Wnt Signaling in Epithelia. Mol. Cell. Biol. 33:2963-2975.
- Grossmann AH, Yoo JH, Clancy J, Sorensen LK, Sedgwick A, Tong Z, Ostanin K, Rogers A, Grossmann KF, Tripp SR, Thomas KR, D'Souza-Schorey C, Odelberg SJ, Li DY. (2013) The small GTPase ARF6 stimulates β-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis. Science Signaling. 6(265):ra14. doi: 10.1126/scisignal.2003398.
- D'Souza-Schorey C, Clancy JW. (2012) Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes and Development. 26: 1287-99.
- Tushir J.S., Clancy J., Warren A., Wrobel C., Brugge J.S., D'Souza-Schorey C. (2010) Unregulated ARF6 activation in epithelial cysts generates hyperactive signaling endosomes and disrupts morphogenesis. Mol. Biol. Cell. 21: 2355-2366.
- Muralidharan-Chari, V., Clancy J.W., Plou C., Romao M., Chavrier P, Raposo G., and D'Souza-Schorey C. (2009) “ARF6 regulated shedding of tumor-derived plasma membrane microvesicles.” Current Biology 19(22):1875-85.
- Muralidharan-Chari V., Hoover H., Clancy J., Schweitzer J., Suckow M., Schroeder V., Castellino F., Schorey J., D’Souza-Schorey C. (2009) ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo. Cancer Research 69: 2201-2209.
- Tushir, J.S. and D’Souza-Schorey C. (2007) ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development. EMBO J. 26: 1806-1819.
- D’Souza-Schorey C and Chavrier P. (2006) ARF proteins: roles in membrane traffic and beyond. Nature Reviews Mol. Cell. Biol. 7: 347-358.
- Palacios F., Schweitzer J., Boshans R.L. and D’Souza-Schorey, C. (2002) ARF6-GTP recruits nm23-H1 to facilitate dynamin-dependent endocytosis during adherens junction disassembly. Nature Cell Biology 4: 929-936.
- Van Aelst L. and D’Souza-Schorey C. (1997) Rho GTPases and signaling networks. Genes and Development 11: 2295-2322.
- D’Souza-Schorey C., Li G., Colombo M.I., and Stahl P.D. (1995) A regulatory role for ARF6 in receptor-mediated endocytosis. Science 267: 1175-1178.