Most cancers become deadly when their cells break free from the initial tumor and infiltrate other organs or tissue, like a wildfire spreading from tree to tree, ultimately overwhelming a forest.
If the fire can be contained to the original spark, the odds of putting it out completely greatly increase. New research helps explain how the flame of cancer grows out of control so that it can be stopped before it spreads, or becomes metastatic. The findings, by Furman University biologist Adi Dubash and four undergraduate students, earned the cover of the June 2019 issue of The Journal of Investigative Dermatology.
Dubash and his students – the study’s first author, Jacqueline Bendrick ’18, Luke Eldredge ’19, Erica Williams ’17 and Nick Haight ’19 – spent three summers testing a theory about cancer metastasis that began with Dubash’s previous research in heart disease.
After a heart attack, proteins signal the growth of fibrous tissue to replace dead heart muscle cells. The proteins work with desmosomes – sticky parts of cells that help connect them to each other – to form patches that help the heart maintain its structural integrity. As a postdoctoral fellow at Northwestern University, Dubash found that when desmosomes are missing, a cell signaling protein called p38 MAPK is more active, leading to more fiber production.
Since cancer cells use similar fiber “highways” to migrate faster and metastasize to other parts of the body, Dubash wondered if this signaling between proteins and desmosomes also occurs in cancer cells.
“And, it does,” he says.
Dubash and his team of students looked at human skin cancer cells, including cells that lacked desmosomes. They scratched the cells to create a wound, a common technique to measure cell migration, and photographed the cells immediately after the scratch and 12 hours later.
Without desmosomes, the signaling by two proteins – p38MAPK and RAC1 – increased, which led the cells to produce more protrusions, or “arms,” so they can efficiently grab on to fiber highways in their environment and move faster,” like laying down a trail of dry kindling in front of a fire.
Bendrick says once the scratch experiment was set up, the results came quickly. “Our first experiment worked beautifully and we got triplicate data within two weeks,” she says. Bendrick is now working in a lab at the Allen Institute for Brain Science in Seattle. While at Furman, she won numerous awards and honors as a student athlete.
The team also discovered that they could return the growth rate to normal by either blocking the signaling or re-introducing desmosome proteins to the cells.
“That was really impactful,” Dubash says.
The research adds to a growing body of work that paints desmosomes as more than cellular glue, but complex structures that regulate cell functions like cell migration, which make them potential targets for drug therapy.
“There’s absolutely a role for desmosomes” in controlling cancer metastasis, Dubash says. “The question is, can we translate this new knowledge into drug therapies that inhibit these biochemical signals.”
Dubash and his current research students, Hunter Alexander ’20 and Tucker Shelton ’22, are continuing this work. “Our current experiments in cancer cells are replicating the same signals seen in heart cells, which is fascinating” Dubash says, “but instead of making fibers to patch muscle, the cancer cells are creating more fibers in their environment as scaffolding to grab onto.”
Bendrick, the study’s first author, says there’s still a lot to understand about desmosomes.
“You can’t make drugs without understanding how this foundational science works,” she says. “There are a lot more pathways desmosomes could affect and more cell behaviors they could play a role in altering,” she says.
Bendrick says her experience running a research project and being first author on a paper definitely gave her an advantage when looking for a job in science. In a series of job interviews, she says potential employers “were very surprised that I had a first-author paper, and that I did it as an undergrad.”
It also cemented her love of research; she plans to apply to a doctoral program in cell and molecular biology. Eldredge is currently pursuing a doctorate in cell biology at the University of Virginia School of Medicine and Williams is pursuing a doctorate in pharmacology at the University of Arizona. Haight tutors biology and math at Greenville Technical College.
The research was funded by a grant from the National Institutes of Health South Carolina IDeA Networks of Biomedical Research Excellence (SC INBRE). Bendrick also received support from a 2017 South Carolina Independent Colleges and Universities Undergraduate Student/Faculty Research Grant, and all the students were supported by Furman University Undergraduate Research Fellowships.
The images of migrating cancer cells were captured by Dubash’s students using a spectral confocal fluorescence microscope, a high-powered piece of technology that was obtained in 2017 by Furman’s Office for Integrative Research in the Sciences through a grant from the Sherman Fairchild Foundation.
Dubash recently scored another SC INBRE grant with bioengineering collaborators at Clemson University. This grant is a return to heart disease research for Dubash. He and Clemson’s Will Richardson will work toward creating a 3-D model of cardiac muscle cells that will more accurately replicate the cells’ natural environment, while allowing for genetic and drug testing that cannot be done as efficiently in whole-animal models.