As tissues form and the body takes its shape in early development, cells move to new areas and transition between different behavioral and functional states. This fundamental process is also co-opted by cancer cells, allowing them to evade therapy, spread through the body and seed new tumors. Fred Hutchinson Cancer Research Center systems biologist Dr. Taran Gujral has received a National Science Foundation CAREER Award to study the molecular networks that govern cells’ ability to make these transitions, with an eye toward designing new ways to intervene in the future.
“The knowledge that we can learn from here hopefully will also help us to understand how we can block some of these changes that happen in disease states,” Gujral said.
The CAREER Award is the NSF’s most prestigious funding source for early-career investigators who have potential to serve as role models in research and education. The five-year, $1.2M award will allow Gujral to introduce two high school students to computational research.
He previously received a three-year award from the American Cancer Society for nearly $800,000, which is allowing him to explore this same cell-state transition in cancer.
The shift from a stationary cell state with specialized functions to a more migratory cell state is called the epithelial-to-mesenchymal transition, or EMT.
“When cells undergo that transition, they become a completely different cell type,” Gujral said.
After the EMT, a cell’s shape, ability to migrate, metabolism, and which genes are switched on have all transformed. It’s an important phenomenon in embryonic development and in wound healing, when cells need to temporarily acquire new functions and the ability to move in order to close a gap.
But certain disease processes activate the EMT, with harmful effects. After undergoing the EMT, cancer cells can move through the body and grow into new tumors. And EMT run amok in wound healing can result in scarring.
“Understanding [the EMT] from the basic science perspective is really critical,” Gujral said, noting that the EMT is driven by the same genes and proteins in disease as it is in normal development and wound healing: “The players are the same, but they just play by different rules.”
By revealing the networks of molecules that cooperate to promote the EMT, Gujral will reveal critical players that could potentially be targeted to reverse the process in disease.
Gujral has shown that no single molecule or molecular pathway controls the EMT. He and his team will take a broader view and work to understand how these pathways cooperate, and how key molecules function within the larger network.
“We’re working toward a computational model that could explain how different signaling pathways crosstalk with each other and ultimately make the decision for a cell to undergo that transition,” he said.
Then, Gujral will apply these findings to manipulate the cell-state transition in myofibroblasts, skin cells which have undergone the EMT. This naturally occurs during normal wound healing, but overactive myofibroblasts can cause scarring by producing too many inflammatory molecules and too much connective tissue. Fibrosis is also a hallmark of many cancer types; in this case, cancer-associated fibroblasts produce excess inflammatory and connective-tissue molecules that create an environment that helps tumor cells survive and grow.
Gujral’s ACS grant supports work examining how the EMT changes how tumor cells respond to different drugs.
“Knowing what kind of state the cancer cells are in can help you better select the drugs to target them,” he said.
Undergoing the EMT often helps cancer cells become resistant to certain drugs, but by reversing this transition, their sensitivity to the treatments can be restored, Gujral noted. Though the project focuses specifically on liver cancer, the principles likely apply to many cancer types, he said.
Education is a key component of every NSF award, and Gujral’s project includes opportunities for young scientists to address interesting scientific questions with computational approaches.
“What I’m really excited about is the opportunity to work with undergrads and high school students,” Gujral said.
Even before receiving his CAREER Award, Gujral took advantage of the Hutch’s programs for young scientists by mentoring two high school students, each of whom have produced their own first-author scientific paper — impressive accomplishments for researchers so early in their careers. He’s also opened his lab to interested high school teachers. The two high school students currently working in his lab are outstanding, he said.
“It’s fantastic,” Gujral said. “I wish [opportunities like] this had existed when I was in high school.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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