3-D imaging and computer modeling capture breast duct development

June 14, 2018, Johns Hopkins University School of Medicine
An image of a developing mammary duct. Credit: Andrew Ewald

Working with hundreds of time-lapse videos of mouse tissue, a team of biologists joined up with civil engineers to create what is believed to be the first 3-D computer model to show precisely how the tiny tubes that funnel milk through the breasts of mammals form.

A report on the model was published April 9 in Developmental Cell. The model employed science and engineering principles commonly used to predict the forces at work on bridges and buildings and "miniaturize" them to use on .

Understanding how such ducts form, the team says, may lend insight into how diseases such as metastatic breast cancers spread throughout the body.

"We learned from this study that cancers would not need to 'invent' cell migration, but only reactivate dormant but normal duct migration programs in the wrong place and wrong time," says Andrew Ewald, Ph.D., professor of cell biology at the Johns Hopkins University School of Medicine and a researcher at the Johns Hopkins Kimmel Cancer Center. Ewald emphasizes that the computer model was created through observations of mouse tissue grown in the laboratory, but because mammalian biology is so highly conserved across species, the same processes are likely applicable to most or all mammals.

Ewald's lab worked with a research team from the University of Waterloo in Canada led by Wayne Brodland, to build the model. The team compared how migrating cells interact with their neighbors and organize into "scaffolding," to the systems of beams that support man-made structures.

"This was an interesting structural engineering problem to solve," says Matthew Perrone, a civil engineering master's student at the Johns Hopkins Whiting School of Engineering. "In addition to determining the forces acting within a finished duct that hold it together, we had to compute the forces that allow it to support itself while still developing."

As the mouse mammary tissues grew breast milk ducts, the research team measured the angles between one cell border and the next and used this info to calculate the relative strength and direction of forces acting on the cells in these tissues.

These cellular scaffolds look similar to a basketball net, says Ewald.

"Imagine an invisible hand pulling on the net, in which the angles between all of the links change such that you can predict where the hand is and what it's doing," he says.

These angles change as a cell moves through a tissue, a process incited by chemical gradients within the cell. Using fluorescent molecules to mark these chemicals, the research team found the signaling proteins RAS, phosphatidylinositol 3-kinase and F-actin concentrate in the front of the cell and watched as these signals prompted the cell to change from a typical shapeless epithelial cell into a unique teardrop shape as they begin to move.

"After seeing this occur hundreds of times, we knew that shape must be important for the biology and the mechanics of the system," says Neil Neumann, lead author on the study and an M.D./Ph.D. candidate at the Johns Hopkins University School of Medicine.

That shape, the researchers found, was a result of a pulling force at the front of the cell and a pushing force at the back—the same forces at work in single cells moving outside of tissues.

"Almost all of cell migration research over the past 50 years has been based on that have been removed from a normal context and placed on a rigid surface such as a petri dish," says Ewald. "Our results reassure us that our understanding of the forces at work on a simple system like a single cell can be applied to more complex environments."

However, Ewald says, a major difference between a cell moving in isolation and one moving through complex living tissue is that for the latter, the cell needs to break and form connections with their neighbors in order to move to their destination.

Ewald's team saw that the cells at the front of the elongating duct replicate to create layer after layer of daughter cells directly below them, like a ball slowly filling in from the outside. To elongate the duct, the cells from the lower layers begin to crawl their way up to the surface, expanding the surface area and the length of the duct.

With all of this information coded in, the initial model was still incomplete, creating structures that sprawled out in all directions, rather than growing directionally into a long, linear tube typical of healthy mammary ducts. "This failure told us that for normal tubes to form, we needed to be some other force at the edge of tubes," Ewald says. Ultimately, the researchers found that the stationary cells in the tissue created fibers that fortify the cell's shape. When the forces created by these fibers were added to the model, the tubes finally elongated.

"It is similar to blowing up a balloon inside of a paper tube. The rigid outer layer directs the expansion," says Ewald.

The researchers say the computer model should enable more multidisciplinary studies showing how cells migrate in healthy organs and provide insight into how diseased cells, such as cancers, may use these processes to spread.

"An exciting part of this interdisciplinary work is that each side of the project informed and enhanced the work of the other," says Neumann. "The experiments that we performed improved the computer model, and the results from the gave us new insights into how the biology worked."

Explore further: First step of metastasis halted in mice with breast cancer

More information: Neil M. Neumann et al. Coordination of Receptor Tyrosine Kinase Signaling and Interfacial Tension Dynamics Drives Radial Intercalation and Tube Elongation, Developmental Cell (2018). DOI: 10.1016/j.devcel.2018.03.011

Related Stories

First step of metastasis halted in mice with breast cancer

December 12, 2013
Cell biologists at Johns Hopkins have identified a unique class of breast cancer cells that lead the process of invasion into surrounding tissues. Because invasion is the first step in the deadly process of cancer metastasis, ...

Cancer cells travel together to forge 'successful' metastases

February 1, 2016
There's apparently safety in numbers, even for cancer cells. New research in mice suggests that cancer cells rarely form metastatic tumors on their own, preferring to travel in groups since collaboration seems to increase ...

Breast cancer cells enticed to spread by 'tumorous environment' as well as genetic changes

October 22, 2012
(Medical Xpress)—A new study from Johns Hopkins researchers suggests that the lethal spread of breast cancer is as dependent on a tumor's protein-rich environment as on genetic changes inside tumor cells.

Prostate cancer cells become 'shapeshifters' to spread to distant organs

August 8, 2017
Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root ...

Recommended for you

Discovery of inner ear function may improve diagnosis of hearing impairment

October 15, 2018
Results from a research study published in Nature Communications show how the inner ear processes speech, something that has until now been unknown. The authors of the report include researchers from Linköping University, ...

Team's study reveals hidden lives of medical biomarkers

October 12, 2018
What do medical biomarkers do on evenings and weekends, when they might be considered off the clock?

Widespread errors in 'proofreading' cause inherited blindness

October 12, 2018
Mistakes in "proofreading" the genetic code of retinal cells is the cause of a form of inherited blindness, retinitis pigmentosa (RP) caused by mutations in splicing factors.

Researchers create a functional salivary gland organoid

October 11, 2018
A research group led by scientists from Showa University and the RIKEN Center for Biosystems Dynamics Research in Japan have, for the first time, succeeded in growing three-dimensional salivary gland tissue that, when implanted ...

Lassa fever vaccine shows promise and reveals new test for immunity

October 11, 2018
Lassa fever belongs to the same class of hemorrhagic fevers as Ebola. Like Ebola, it has been a major health threat in Western Africa, infecting 100,000-300,000 people and killing 5,000 per year. A new vaccine against both ...

Genetically engineered 3-D human muscle transplant in a murine model

October 10, 2018
A growing need for tissues and organs in surgical reconstruction is addressed by the promising field of tissue engineering. For instance, muscle atrophy results from severe traumatic events including deep burns and cancer, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.