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Tissue Geometry Plays Crucial
Role in Breast Cell Invasion
Apropos of National Breast Cancer
Awareness month, researchers with the U.S. Department of Energy’s Lawrence
Berkeley National Laboratory (Berkeley Lab) have created a first-of-its-kind
model for studying how breast tissue is shaped and structured during
development. The model may shed new light on how the misbehavior of only a
few cells can facilitate metastatic invasion because it shows that the
development of breast tissue, normal or abnormal, is controlled not only by
genetics but also by geometry. Though created specifically for the study of
breast tissue, this model should also be applicable to the study of tissue
development in other organs as well.
October 13, 2006. Source:
Berkeley Lab News Releases
“Our results reveal that tissue geometry can control the morphogenesis of
breasts and other organs by defining the local cellular branching
microenvironment,” said Bissell, a Distinguished Scientist with Berkeley
Lab’s Life Sciences Division, who was the principal investigator for this
study. “This finding is important not only for understanding how tissue and
organs get their organized shapes and patterns, but may in the future reveal
mechanisms to control cancer invasion and metastasis.”
In a paper published in the October 13, 2006 issue of the journal Science,
Bissell and her collaborators describe a study in which the branching of
mouse epithelial tubules (hollow tubes made from epithelial cells that form
the network of milk ducts in the mature female breast) in culture were
subjected to control through a three-dimensional micropatterned assay. Using
a special algorithm to quantify the extent of branching, the researchers
found that the geometric shape of the tubules determines where branching
takes place. This may potentially affect where and how a malignancy spreads.
The paper is entitled: Tissue Geometry Determines Sites of Mammary Branching
Morphogenesis in Organotypic Cultures. Co-authoring the paper with Bissell
were Celeste Nelson and Jamie Inman, both members of Bissell’s research
group, and Daniel Fletcher and Martijn VanDuijn, from the University of
California at Berkeley’s Bioengineering Department. Fletcher also holds an
appointment with Berkeley Lab’s Physical Biosciences Division.
In mammals, breast tissue begins to morph into milk glands at the onset of
puberty. In this process, called branching morphogenesis, epithelial cell
tubes begin to migrate outward, invading the surrounding pad of fat cells to
form a widely branched tree of milk ducts. Branching morphogenesis is known
to involve a complex interplay of both intracellular and extracellular
signals that within the context of the tissue determines precisely where new
branches are initiated.
Said co-author Nelson, a post-doctoral bioengineer who will soon have her
own research group at Princeton University, “One group of cells within a
tubule is instructed to form a branch or to bifurcate, whereas a neighboring
group is not. While branching morphogenesis is common to many organs,
including the lung, kidney and salivary gland, we still do not have a
precise understanding of how spatial positioning is determined. Given that
the mammary ductal network branches out from pre-existing epithelial
tubules, we hypothesized that the position of cells within a tubule might
provide contextual information to instruct branch site initiation.”
Bissell is one of the leading proponents of the idea that a cell’s genetic
information is supplemented by contextual information encoded within the
microenvironment that surrounds the cell. To define the role of positional
context, she and Nelson developed a 3-D micro patterned assay for mammary
epithelial branching morphogenesis. This assay enabled them to control the
initial geometry of epithelial tubules and to quantify the positions at
which they branched.
In their studies, Bissell, Nelson and their colleagues engineered epithelial
tubules of defined geometry by embedding functionally normal mouse mammary
epithelial cells in cavities of a collagen gel. The epithelial cells formed
hollow tubules, according to the size and shape of the collagen cavities.
These tubules began branching out into the gel within 24 hours after being
treated with epidermal growth factor. To quantify branching and to represent
its magnitude and position, the researchers stained the cell nuclei with
fluorescent dye and imaged them using confocal microscopy.
“We confirmed that the position of branching depended on the initial
geometry of the tubule,” said Nelson. “Increasing the length of the tubules
increased the magnitude of branching, although cells still branched
exclusively from the ends. Curved tubules branched preferentially from the
convex side of the curve. Asymmetric branching was also observed in
bifurcated tubules and trees, which preferentially branched from distal
positions.”
The process of normal branching morphogenesis is precise and quantitative,
but invasionary; when something goes wrong the process may lend itself to
metastasis. With this demonstration of how the normal function of branching
morphogenesis is controlled, Bissell believes researchers can now look for
ways in which faulty tubule geometry leads to malignancy.
“In breast cancer, it is most often metastasis rather than the primary tumor
that kills a patient,” said Bissell. “We have learned something really
dramatic about the regulation of normal branching morphogenesis and this
should help us understand how and why things go wrong. Our next step is to
put pre-malignant cells – cells that are already losing their way but are
not yet malignant – into our model and see what happens. When we do, perhaps
this will provide us with new ideas for intervening and preventing
pre-malignant cells from becoming fully malignant.”
This research was funded in part by the U.S. Department of Energy, the
National Institutes of Health, and the U.S. Department of Defense.
Berkeley Lab is a U.S. Department of Energy national laboratory located in
Berkeley, California. It conducts unclassified scientific research and is
managed by the University of California. Visit our Website at www.lbl.gov.
Additional Information
For more information about the research of Mina
Bissell, visit her Website at
http://www.lbl.gov/lifesciences/BissellLab/main.html
For more information about the research of Daniel Fletcher, visit his
Website at
http://fletchlab.berkeley.edu/people.htm
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