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Membrane Trafficking and Signal Integration in Disease

Crislyn D'Souza-Schorey

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Professor and Chair, Biological Sciences
Ph.D., University of Texas Health Science Center at San Antonio
Postdoctoral, Washington University School of Medicine

 

A major focus of the laboratory is to define how altered regulation of signaling pathways that govern cell motility contribute to cancer initiation and progression. The ultimate goal is to utilize this information for the development of novel diagnostic and therapeutic strategies. Our research employs a multifaceted approach involving the use of two and three-dimensional cell model systems, in addition to animal models and interrogation of clinical samples. Ongoing lines of investigation include:

Early events in epithelial cancer progression. We utilize organotypic models to study the development of the basic structural units of epithelial glandular tissues, namely, cysts and tubules. These are also the sites from where most cancers develop. Ongoing projects investigate how the matrix microenvironment and extracellular signals such as Wnts and Receptor tyrosine kinase-activating growth factors, through coordinated changes in membrane traffic and the actin cytoskeleton, regulate epithelial glandular architecture. This line of investigation focuses largely on a downstream signaling axis that is regulated by the activation of ARF6, a small Ras-like GTP-binding protein, and how perturbations to this axis can lead to the acquisition of oncogenic phenotypes.

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Molecular mechanisms of tumor cell invasion. Tumor cell invasion is an essential step in metastasis, the major life threatening clinical manifestation of cancer. The laboratory is interested in mechanisms that lead to the formation of microvesicles and invadopodia, two distinct conduits of invasion used by tumor cells. Ongoing projects focus on the characterization of invasive microvesicles (oncosomes) released by tumor cells, including mechanisms involved in their biogenesis and their ability to carry out the horizontal transfer of bioactive molecules to modulate the tumor microenvironment. We are also developing clinically adaptable methods that allow a quantitative analysis of tumor-derived microvesicles given their potential as circulating biomarkers and platforms for personalized therapy.

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Signaling pathways in rare neurodegenerative diseases. A second line of investigation involves understanding the cellular basis of pathogenesis associated with rare neurodegenerative disorders such as Huntington’s Disease (HD) and Niemann-Pick Type C (NPC). Both diseases are linked to specific mutations that result in misfolded proteins. Ongoing projects investigate the basis by which certain signaling pathways which are hyper-activated in cancers, such as those coupled to ARF6 and its associated regulatory molecules, appear to be repressed in degenerative disease.

 

Selected Publications

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, Li G. (2013) Endocytosis and the Regulation of Cell Signaling, Cell Adhesion, and Epithelial to Mesenchymal Transition in Cancer. Book Chapter 6 in Vesicle Trafficking In Cancer.  Eds: Yosef Yarden, Gabi Tarcic, New York, NY: Springer.

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.

Monteleon CL, Sedgwick A, Hartsell A, Dai M, Whittington C, Voytik-Harbin S, D'Souza-Schorey C.  (2012) Establishing Epithelial Glandular Polarity: Interlinked roles for ARF6, Rac1 and the matrix microenvironment.  Mol. Biol. Cell. 23: 4495-4505.

Johnson R.I., Sedgwick A., D'Souza-Schorey, C., Cagan R.L. (2011) Role for a Cindr-ARF6 axis in patterning emerging epithelia. Mol. Biol. Cell. epub ahead of print.  doi:10.1091/mbc.E11-04-0305.

Schweitzer J.K., Sedgwick A.E., D'Souza-Schorey C.  (2011) ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis.  Semin. Cell. Dev. Biol. 22(1):39-47.  

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., Sedgwick, A. and D'Souza-Schorey C. (2010) Microvesicles: Mediators of extracellular communication during cancer progression. J. Cell. Sci. 123: 1603-1611. Invited Commentary.
 
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.
 
Schweitzer J., Pietrini S., D’Souza-Schorey C. (2009) ARF6-mediated endosome recycling reverses lipid accumulation defects in Niemann-Pick Type C Disease. PLoS One 4: e5193.

Sakurai-Yageta M., Recchi C., Le Dez G., Sibarita J., Daviet L., Camonis J., D’Souza-Schorey C., Chavrier P. (2008) The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA. J. Cell. Biol. 181: 985-998.

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.

Lynch E.A., Stall J., Schmidt G., Chavrier P., D’Souza-Schorey C. (2006) Proteasome-mediated Degradation of Rac1-GTP during Epithelial Cell Scattering. Mol. Biol Cell. 17: 2236 -2243.

Hoover, H., Muralidharan, V. D’Souza-Schorey, C. (2005) Role of the ARF6 GTPase in Tumor Cell Invasion. Methods Enzymol. 404: 134-147.

Schweitzer J., Burke, E., Goodson H., D’Souza-Schorey, C. (2005) Endocytosis resumes during late mitosis and is required for cytokinesis. J. Biol. Chem. 280: 41628-41635.

D’Souza-Schorey, C. (2005) Disassembling adherens junctions: Breaking up is hard to do. Trends in Cell Biol. 15: 19-26.

Palacios F., Tushir J.S., Fujita Y., and D’Souza-Schorey, C. (2005) Lysosomal targeting of E-cadherin: A unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions. Mol. Cell. Biol. 25: 389-402.

Tague S., Muralidharan V., and D’Souza-Schorey C. (2004) ARF6 regulates tumor cell invasion via the activation of the MEK/ERK signaling pathway Proc. Natl. Acad. Sci. USA. 101: 9671-9676.

Palacios F. and D’Souza-Schorey C. (2003) Modulation of ARF6 and Rac1 activities during epithelial cell scattering. J. Biol. Chem. 278:17395-17400.

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.

Schwetizer J., and D’Souza-Schorey, C. (2002) Localization and activation of ARF6 during mitosis. J. Biol. Chem. 277: 27210-27216.

Peters P*., Ning K.*, Palacios F., Kazantsez A., Thompson L., Bates G., and D’Souza-Schorey C. (2002) Arfaptin 2 regulates the aggregation of mutant huntingtin. ( *equal contribution) Nature Cell Biology 3:240-245.

Muchowski P., Ning K., D’Souza-Schorey C., and Fields S.F (2002) Requirement of an intact microtubule cytoskeleton for aggregation of huntingtin exon 1. Proc. Natl. Acad. Sci. (USA) 99:727-732.

Palacios F., Price L., Schweitzer J., Collard J., and D’Souza-Schorey, C. (2001) An essential role for ARF6-regulated membrane traffic in adherens junction assembly and epithelial cell migration. EMBO J. 20: 4973-4986.

Franco M., Peters P.J., Boretto J., Van Donselaar E., D’Souza-Schorey C., and Chavrier P. (1999) EFA6, a novel exchange factor for ARF6 coordinately regulates membrane trafficking and actin organization. EMBO J. 18: 1480-1491.

D’Souza-Schorey C., Van Donselaar E., Hsu V., Yang C.Z., Stahl P.D. and Peters P.J (1998) ARF6 targets recycling endosomal vesicles to the plasma membrane: Insights from an ultrastructural investigation. J. Cell. Biol. 140: 603-616.

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.