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dc.contributor.advisor Sherwood, David R en_US
dc.contributor.author Hagedorn, Elliott Jennings en_US
dc.date.accessioned 2012-09-04T13:14:47Z
dc.date.available 2014-08-25T04:30:04Z
dc.date.issued 2012 en_US
dc.identifier.uri http://hdl.handle.net/10161/5770
dc.description Dissertation en_US
dc.description.abstract <p>Basement membrane (BM) is the thin, dense, highly cross-linked form of extracellular matrix that underlies all epithelia and endothelia, as well as surrounds muscle, nerve and fat. These sheet-like networks function as physiological barriers to maintain tissue homeostasis. During normal developmental processes and immune surveillance, cells invade through BM to establish tissues and fight infection. Similarly, metastatic cancer cells are thought to co-opt normal programs for BM transmigration as they spread from primary tumors and colonize distant tissues. The difficulty of visualizing cell-BM interactions during invasion in vivo has left the cellular and molecular mechanisms used to breach BM undefined. Specialized F-actin-rich matrix-degrading membrane protrusions, termed invadosomes, have been described in cultured invasive cell lines for more 30 years. Invadosomes are hypothesized to mediate BM penetration during cancer metastasis. Despite promising advances in intravital imaging technologies, however, invadosomes have yet to be observed in cells transmigrating BM in vivo, leaving their physiological relevance unclear. Anchor cell invasion in C. elegans is a simple in vivo model of cell invasion that allows for combined visual and genetic analysis of BM transmigration. In this dissertation I develop high-resolution time-lapse imaging approaches to understand the dynamic interactions that occur at the AC-BM interface during invasion. Through the course of this work we identify an integrin-based mechanism that polarizes the AC towards the BM. We further discover protrusive F-actin-based invadosome structures that mediate BM breach during anchor cell (AC) invasion. We find that in most cases only one or two invadosomes penetrate the BM and then transform into an invasive protrusion that guides the AC through a single BM gap. Using genetics and quantitative single-cell image analysis we characterize several molecular regulators of invadosome formation in vivo. Our findings establish an essential role for invadosomes during BM transmigration in vivo, and support the idea that these structures are a core, conserved element of a normal invasive cellular strategy activated during cancer metastasis.</p> en_US
dc.subject Biology en_US
dc.subject Developmental biology en_US
dc.subject Cellular biology en_US
dc.subject anchor cell en_US
dc.subject basement membrane en_US
dc.subject C. elegans en_US
dc.subject cell invasion en_US
dc.subject invadosomes en_US
dc.subject time-lapse microscopy en_US
dc.title Imaging the Cell-Basement Membrane Interface during Anchor Cell Invasion in C. elegans en_US
dc.type Dissertation en_US
dc.department Genetics and Genomics en_US
duke.embargo.months 24 en_US

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