A grant from the National Cancer Institute will advance researchers from the USC Viterbi School of Engineering and the Keck School of Medicine of USC in their fight against colorectal cancer.
Stacey Finley, holder of the Gordon S. Marshall Early Career Chair and an assistant professor in USC Viterbi’s Department of Biomedical Engineering, and Shannon Mumenthaler, a Keck USC assistant professor of medicine at the Lawrence J. Ellison Institute for Transformative Medicine of USC, are recipients of a $3.1 million grant from the National Cancer Institute.
The funds will be divided equally between Finley, Mumenthaler, and a third researcher, Paul Macklin, an associate professor at the Indiana University School of Informatics, Computing, and Engineering. This award will support their research in the use of computer simulations to explore the complex cellular interactions that fuel the growth and spread of tumors in the body.
Finley, an expert on studying cellular metabolism in a single cell, is building models to predict the reaction networks that occur inside cancer cells and fibroblasts – cells that support and interact with these cancerous cells. Mumenthaler specializes in creating cell cultures that mimic bodily organs, which can be used to simulate the conditions of a tumor in order to run tests.
Cancer cells are characterized by continuous, unchecked growth. One hypothesis suggests this may be due in part to their more effective use of nutrients like sugars and oxygen. By modeling the interactions between two cell types and how they metabolize nutrients, Finley and Mumenthaler, along with Macklin, hope to explain why this occurs and determine how to stop it.
Finley, Macklin, and Mumenthaler’s research focuses on colorectal cancer. Over 1.3 million people in the United States are living with colorectal cancer, according to the National Cancer Institute. The disease is the third-leading cause of cancer death in men and women in the country, with about 90 percent of those diagnosed with metastatic disease dying within 5 years.
“Colorectal cancer patients have a high death rate and they often develop resistance to the current treatments,” Finley said. “Thus, there is a real need for more effective therapies.”
In the first phase of the research project, Dr. Finley’s lab will build detailed mathematical models of the metabolism in cancer cells and fibroblasts. The next phase focuses on adopting principles from Finley’s research to Macklin’s PhysiCell system, which simulates cellular activity. The team will then be able to run simulations that mimic how various structures and molecules inside a cell interact during tumor formation and spread. The team will then focus on verifying the software’s predictions against real tissues in the lab.
This phase will take place inside “mini-organs” – called organoids – created in Mumenthaler’s lab. These objects are created by applying special growth factors to cellular “blobs” that cause them to form into structures that resemble rudimentary organs. The use of organoids is an increasingly popular method in biomedical research that allows scientists to safely experiment on highly accurate tissue types without risking patients’ health.
“My models of intracellular metabolism are embedded in PhysiCell, where Macklin will perform hundreds of simulations to identify how the overall growth of the tumor can be halted,” Finley explained. “Finally, we test the model predictions about the most promising candidates for inhibiting tumor growth in the physically realistic experimental models of tumor growth that Dr. Mumenthaler’s lab builds.”
If the simulations suggest a specific compound may reduce tumor growth, the organoids will also allow the researchers to try it on real cells. But only in a few select cases.
“The big advantage of conducting research in a computerized environment is you can afford to fail,” Macklin said. “By comparison, lab research is extremely expensive in terms of time and money.”
He added: “If you’ve got the freedom to experiment, you can really narrow your ideas down until you’re spending your experimental budget on the most promising ideas. You’re not trying to go all the way to a clinical trial phase and then failing after spending millions or billions of dollars.”
Mumenthaler agrees. “We’re combining mathematical models with experimental data to computationally explore and ultimately narrow down the infinite treatment options first, followed by experimental validation of the most promising strategies.”
According to Finley, USC’s emphasis on interdisciplinary collaboration has supported her pursuit of impactful research.
“I’m part of the Michelson Center, which focuses on convergent bioscience, by bringing researchers from different departments together to tackle important biological questions,” she said.
By drawing from a diverse network of scientists, engineers, and students, the USC Michelson Center for Convergent Bioscience fosters biomedical discovery, innovation and real-world solutions to fast-track detection and cures for diseases ranging from microbial infections to Alzheimer’s and cancer.
Last fall, USC opened the hub for this initiative, Michelson Hall — a 190,000 square-foot, high-tech research facility supported by a $50 million gift from retired spinal surgeon Gary K. Michelson and his wife, Alya Michelson.
This collaborative effort has also connected her with Mumenthaler. Their joint involvement in the Ellison Institute for Transformative Medicine at USC, which explores different ways to tackle cancer and other diseases using insight from a range of other academic disciplines, has made it easier to collaborate on this current project.
“The Ellison Institute and the Michelson Center have helped to break down the physical and abstract barriers that separate traditional departments from each other to foster innovative and transformative research,” Mumenthaler said.
Finley hopes to use this grant to continue her research and improve the modeling process for tumor growth. “Our integrative modeling and experimental approach can help to address the need for more effective therapies to treat cancer,” she said.