One of the fundamental steps in the formation of most organs is the assembly of cells into epithelial layers;simple epithelial cells share a common polarity, are linked by apical junctions and share a basal basement membrane. However, epithelia can undergo extensive remodeling during development, growth, or wounding, with constituent cells changing shape or moving. Some remodeling- specific behaviors of normal epithelia, such as the loss of cell adhesion, are reminiscent of cancer cells, the vast majority of which originate from epithelial cells. We recently discovered epithelial remodeling events in C. elegans that provide a system for understanding the genetic control of remodeling events, and that might provide insight into how epithelial-derived cells could be controlled in disease. The remodeling events in C. elegans transform two simple epithelial cells into ring-shaped cells. The events begin when a dorsal cell is signaled through the Notch pathway to become invasive. At the same time, a tract of laminin appears on the lateral interface between two, underlying ventral cells, perpendicular to the basal, basement membrane beneath these cells. The invasive cells spread onto the laminin tract, moving between the ventral cells until they reach the ventral basement membrane. Thus, the major epithelial cell behaviors in this system include (a) regulated changes in adhesion to neighboring cells and to the basement membrane, (b) cell invasion, (c) creation of invasion paths, and (d) reintegration into the surrounding epithelium following invasion. We exploit unique features of C. elegans biology that provide powerful tools to dissect the mechanisms involved in remodeling. We propose experiments to detect signaling between the invasive cells and the tract-forming cells, genetic screens to identify proteins required for the intraepithelial deposition of laminin, a reverse genetic approach to identify Notch targets required for invasion, and a system to study how the invasive cells are reintegrated into the epithelium.

Public Health Relevance

Most human cancers are derived from epithelial cells, and some traits of cancer cells resemble unregulated, behaviors of normal epithelia that remodel during development, growth and wound repair. This project uses the model system C. elegans to identify, and understand the functions of, genes that normally control epithelial remodeling. These studies are expected to provide new insights into normal development, and may provide tools and strategies for controlling transformed epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098583-03
Application #
8535173
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$507,265
Indirect Cost
$214,921
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Rasmussen, Jeffrey P; Feldman, Jessica L; Reddy, Sowmya Somashekar et al. (2013) Cell interactions and patterned intercalations shape and link epithelial tubes in C. elegans. PLoS Genet 9:e1003772
Rasmussen, Jeffrey P; Reddy, Sowmya Somashekar; Priess, James R (2012) Laminin is required to orient epithelial polarity in the C. elegans pharynx. Development 139:2050-60