Research - The basic
science of cancer and birth defects
We study
invasive cell behavior using molecular biology,
genetics, cell biology, and biochemistry. My
laboratory has established the border cells in
the Drosophila ovary as a model system for a
systematic, forward genetic approach to study
invasive cell behavior and epithelial to mesenchymal
transitions.
Migrating border cells in the
Drosophila ovary labeled with GFP
Border cells (arrow) shown migrating through the
cluster of nurse cells toward the oocyte (white,
yolk-filled cell) within an egg chamber.
High magnification view of migrating border cells
labeled with rhodamine phalloidin to visualize
filamentous actin (red), anti-beta-galactosidase
antibody staining to reveal the nuclei (blue)
and anti-focal adhesion kinase (green).
What is an epithelial to mesenchymal transition
and why study it?
Epithelial cells are the
cells that line virtually every organ in your body and
85% of cancers derive from epithelial cells. Epithelial
cells are tightly connected to each other through a
variety of cell-cell junctions and they are polarized,
with distinct apical and basolateral sides. During embryonic
development epithelial cells sometimes dissolve their
junctions with their neighbors and become mesenchymal.
Mesenchymal cells have a less rigid shape and are more
likely to be motile. Epithelial to mesenchymal transitions,
as well as the reverse process, are extremely important
for normal development. In addition, these transitions
are important in wound healing, and tumor cells that
develop from epithelial cells must transform into motile
cells in order to metastasize.
Our goal is to
identify the changes in gene expression, cell adhesion
and cytoskeletal organization that are required for
the epithelial to mesenchymal transition in order to
understand this process at a biochemical level.
What are the border cells and why study
them?
The border cells develop
initially as part of the epithelium of 1100 follicle
cells, which surround the cluster of 15 nurse cells
and one oocyte in a structure known as an egg chamber.
Eventually the nurse cells will contribute all of the
cytoplasm to the oocyte which will mature into an egg.
The follicle cells form the egg shell membranes and
secrete signaling proteins that help to pattern the
egg. During stage 9 of oogenesis, the border cells undergo
an epithelial to mesenchymal transition and begin migration
through the nurse cell cluster. The border cells stop
migrating when the reach the oocyte where they normally
function to make a pore in the eggshell through which
the sperm will enter at fertilization and to secrete
the TSL
protein which is necessary for normal head development
in the embryo after fertilization.
The border cells are a
simple example of an epithelial to mesechymal transition,
and the only one that is being studied using a systematic
genetic approach.
An egg chamber from a mutant in which border cell
migration is inhibited.
What do we know about border cell migration?
Numerous genetic screening approaches
have allowed us to identify over a dozen genes that
are required for border cell migration. We have learned
that there are at least three extracellular signals
that must impinge upon the border cells in order for
them to migrate correctly. A steroid hormone, edcysone,
appears to control when the cells migrate and coordinate
this behavior with other events that occur at the same
time in development. A cytokine is produced in a pair
of cells at the center of the border cell cluster, called
the polar cells, and this activates the JAK/STAT signaling
pathway in the surrounding cells. This JAK/STAT signal
determines which cells become migratory and invasive.
In addition there is a growth factor, called PVF1, that
is found at highest levels in the oocyte and this protein
contributes to guiding the border cells to the correct
location. We are continuing to carry out new types of
genetic screens in order to learn more about the molecular
mechansims that control border cells migration as well
as the effects that these signaling pathways have on
cell adhesion and the cytoskeleton. Finally in collaboration
with the lab of Honami Naora at the MD Anderson Cancer
Center, we are investigating whether the genes we identify
in Drosophila also contribute to the migratory behavior
and metastatic potential of human ovarian cancer cells.
For more information, please see our publications.
