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 #
5R01GM079320-03
Application #
7589645
Study Section
Intercellular Interactions (ICI)
Program Officer
Flicker, Paula F
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$287,820
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
Hartman, Jessica H; Smith, Latasha L; Gordon, Kacy L et al. (2018) Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci Rep 8:8359
Cáceres, Rodrigo; Bojanala, Nagagireesh; Kelley, Laura C et al. (2018) Forces drive basement membrane invasion in Caenorhabditis elegans. Proc Natl Acad Sci U S A 115:11537-11542
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
Kelley, Laura C; Wang, Zheng; Hagedorn, Elliott J et al. (2017) Live-cell confocal microscopy and quantitative 4D image analysis of anchor-cell invasion through the basement membrane in Caenorhabditis elegans. Nat Protoc 12:2081-2096
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
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
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:

Showing the most recent 10 out of 34 publications