Our long-term goal is to elucidate the genetic networks that direct cell invasion through basement membranes, the dense, sheet-like extracellular matrix that surrounds most tissues. The mechanisms that cells employ to cross basement membranes in vivo remain poorly understood, as these invasions most often occur in complex environments that are difficult to study. We are thus dissecting the process of anchor-cell (AC) invasion into the vulval epithelium in the visually and genetically accessible model organism Caenorhabiditis elegans. AC invasion involves: (1) the attachment of the AC to the basement membrane, (2) its polarization towards the basement membrane, (3) the generation and reception of a chemotactic signal(s) that stimulates invasion, (4) the precise removal of the basement membrane and (5) transit through the basement membrane. We have discovered a novel role for the netrin pathway in directing the polarization of the AC's invasive cellular processes towards the basement membrane. We have also identified a specific isoform of the C. elegans fos transcription factor, fos-1b, which inhibits AC invasion, perhaps by blocking fos-1a activity, an isoform that promotes basement membrane removal during AC invasion. Finally, we have conducted a pilot screen using a database generated from previous whole genome RNAi screens and identified five additional genes that promote AC invasion, four of which have not previously been implicated in regulating cell invasion. Integrating cellular, genetic, and molecular approaches, our proposed work will: 1) elucidate a new role for netrin signaling in polarizing an invasive cell, 2) determine the mechanisms by which fos-1b inhibits AC invasion, and 3) characterize the function of new genes identified in our RNAi database screen that specifically promote removal of the basement membrane during AC invasion. Cell invasions through basement membranes play crucial roles during normal development and are essential for leukocyte trafficking to sites of infection and injury. Uncontrolled cell- invasive activity is also associated with a number of deadly diseases, including cancer and rheumatoid arthritis. The proposed work will advance our understanding of the fundamental mechanisms controlling cell- invasive behavior and thus has a strong potential to lead to new treatment strategies for a number of human diseases associated with unregulated cell-invasive activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079320-04
Application #
7796698
Study Section
Intercellular Interactions (ICI)
Program Officer
Flicker, Paula F
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$284,942
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Naegeli, Kaleb M; Hastie, Eric; Garde, Aastha et al. (2017) Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain. Dev Cell 43:403-417.e10
Linden, Lara M; Gordon, Kacy L; Pani, Ariel M et al. (2017) Identification of regulators of germ stem cell enwrapment by its niche in C. elegans. Dev Biol 429:271-284
Hastie, Eric L; Sherwood, David R (2016) A new front in cell invasion: The invadopodial membrane. Eur J Cell Biol 95:441-448
Morrissey, Meghan A; Jayadev, Ranjay; Miley, Ginger R et al. (2016) SPARC Promotes Cell Invasion In Vivo by Decreasing Type IV Collagen Levels in the Basement Membrane. PLoS Genet 12:e1005905
McClatchey, Shelly Th; Wang, Zheng; Linden, Lara M et al. (2016) Boundary cells restrict dystroglycan trafficking to control basement membrane sliding during tissue remodeling. Elife 5:
Maurer, Laura L; Yang, Xinyu; Schindler, Adam J et al. (2016) Intracellular trafficking pathways in silver nanoparticle uptake and toxicity in Caenorhabditis elegans. Nanotoxicology 10:831-5
Lohmer, Lauren L; Clay, Matthew R; Naegeli, Kaleb M et al. (2016) A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation. PLoS Genet 12:e1005786
Sherwood, David R (2015) A developmental biologist's ""outside-the-cell"" thinking. J Cell Biol 210:369-72
Matus, David Q; Lohmer, Lauren L; Kelley, Laura C et al. (2015) Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression. Dev Cell 35:162-74
Clay, Matthew R; Sherwood, David R (2015) Basement Membranes in the Worm: A Dynamic Scaffolding that Instructs Cellular Behaviors and Shapes Tissues. Curr Top Membr 76:337-71

Showing the most recent 10 out of 31 publications