Florida State University researchers to lead $2.8 million study examining how physical cell changes drive pancreatic cancer progression
Florida – Florida State University researchers are leading a new $2.8 million study aimed at understanding how physical changes inside pancreatic cells may help one of the deadliest forms of cancer grow and spread.
The research, supported by a grant from the National Cancer Institute, will bring together scientists from the FSU College of Medicine and the FAMU-FSU College of Engineering. Their focus will be pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer and the third-leading cause of cancer deaths in the United States.
Instead of looking only at genes and biochemical activity, the researchers will examine the physical structure of cells and how those structures change as pancreatic cancer becomes more advanced. They want to determine whether changes in the shape and organization of cells are simply signs of the disease or whether they actively contribute to tumor growth and the spread of cancer.
The team will use human-derived pancreatic organoids, which are miniature three-dimensional models of pancreatic tissue grown in laboratories. These models will allow researchers to recreate structural features found in human tumors and study the disease at different stages, from normal pancreatic tissue to primary tumors and metastatic cancer.
One of the central features being studied is a small hollow space inside the organoid known as the lumen. In normal pancreatic organoids, the lumen sits in the center and is surrounded by a relatively thin layer of cells. The arrangement resembles the basic structure of a healthy pancreatic duct.
That structure changes as cancer develops.
“Primary tumor organoids still have a lumen, but the surrounding cell layer becomes much thicker,” said grant co-investigator Jerome Irianto, assistant professor at the College of Medicine. “In metastatic organoids, the central lumen collapses and is replaced by multiple small lumen-like structures, resembling the disorganized architecture seen in advanced pancreatic tumors. This led us to ask two important questions: What drives these structural changes, and what are the consequences for cancer progression?”
Those questions are at the heart of the new research.
The lumen is not simply an empty space. Its shape and size depend partly on the movement of ions and water through the surrounding cells. As ions move into the lumen, water follows. The resulting fluid helps maintain pressure and creates forces that affect the cells around it.
The researchers believe that when the normal movement of ions and water is disrupted, the physical environment inside the organoid also changes. That could alter how neighboring cells behave and how they respond to mechanical pressure.
“A major factor driving the collapse of the lumen is the loss of ion transport that normally helps build pressure inside it, almost like filling a balloon,” said mechanobiologist Tristan Driscoll, assistant professor at the FAMU-FSU College of Engineering and a co-investigator on the grant. “When that pressure changes, it also changes the mechanical forces experienced by the surrounding cells and how those cells sense and respond to those forces.”
Previous work from the Irianto Lab has already pointed toward a possible connection between ion and water transport and the changing structure of pancreatic tumors.
Genes responsible for producing ion and water channels are found at lower levels in pancreatic tumor organoids than in normal pancreatic cells. The researchers have also found that expression of those genes drops further as tumors progress and spread.
The new study will investigate whether that decline helps explain the increasingly disorganized structure seen in advanced pancreatic cancer.
Researchers will measure the forces that develop between neighboring epithelial cells as well as forces transferred to the nuclear envelope, the structure surrounding a cell’s DNA. The goal is to understand how changes in pressure inside the lumen can travel through cells and eventually influence their behavior.
A major part of the project will focus on a protein called yes-associated protein, or YAP.
YAP is sensitive to physical forces inside cells. Under normal conditions, it remains outside the nucleus in an inactive state. But when cells experience changes in mechanical forces or become compressed, YAP can move into the nucleus and become active.
Once inside the nucleus, YAP can turn on genes involved in cell growth, survival and other behaviors that can be important in cancer.
The Irianto Lab will use gene-editing techniques to examine how changes in ion and water transport interact with lumen structure and YAP activity. By changing these systems and observing what happens, the researchers hope to identify links between the physical environment of pancreatic cells and the progression of cancer.
The study could be particularly important because pancreatic ductal adenocarcinoma remains extremely difficult to treat.
The disease accounts for more than 80% of pancreatic cancer cases, and its five-year survival rate is around 13%. Many patients are diagnosed when their tumors can no longer be removed through surgery or when the cancer has already grown into nearby tissues or spread to other parts of the body.
Chemotherapy, surgery and radiation remain among the standard approaches used against pancreatic cancer, but traditional treatments have not produced major improvements in survival rates.
The researchers hope that examining cancer from a physical and mechanical perspective could eventually point toward new treatment opportunities.
“Our goal is to reveal new vulnerabilities in pancreatic cancer that could shape future treatment strategies,” Irianto said. “Despite advancements in care, this continues to be an especially deadly disease that kills tens of thousands of people every year. The better we understand how this works within cells, the better we will be at stopping it.”
The project is also notable for the range of expertise involved. Irianto and Driscoll will collaborate with researchers from other institutions and fields, including mathematical modeler Katarzyna Rejniak of the Moffitt Cancer Center, pancreatic cancer biologist Chang-il Hwang of UC Davis and pathologist Jose I. Diaz of the FSU College of Medicine.
The researchers will combine engineering, cell biology, cancer biology, mathematical modeling and pathology. That broad approach is intended to provide a more complete picture of what happens inside pancreatic tumors.
Cancer research often focuses heavily on genetic mutations and biochemical pathways. Those areas remain important, but the FSU-led team is examining another layer of the disease: the physical environment surrounding and inside cancer cells.
The researchers want to understand how pressure, cell shape, fluid movement and mechanical forces interact with biological signals. Their work could help explain why pancreatic cells become increasingly disorganized as tumors advance and why those changes may be linked to more aggressive disease.
The use of pancreatic organoids will allow the team to study these changes in three-dimensional structures that more closely reproduce key features of pancreatic tissue than traditional two-dimensional cell cultures.
Over the course of the research, the team will examine the progression from normal tissue to primary tumors and eventually metastatic structures. By comparing these stages, scientists can look for changes that appear as the cancer becomes more aggressive.
The $2.8 million National Cancer Institute grant will support the work as the researchers investigate these questions. Their findings may not immediately translate into a new treatment, but the project is intended to uncover vulnerabilities that could eventually guide future strategies against pancreatic cancer.
For FSU, the award also brings together two of its major research strengths. Scientists from the College of Medicine will work alongside researchers in the FAMU-FSU College of Engineering, creating a collaboration that connects medical research with the study of mechanical forces and engineering principles.
The researchers are ultimately trying to understand something deceptively simple: how a change in the physical structure of a cell can influence what that cell does.
In pancreatic cancer, that question could have major consequences. If changes in fluid pressure, cell organization and mechanical signaling help tumors survive, grow or spread, understanding those changes could give scientists another path toward stopping the disease.
The study will therefore look beyond cancer cells as collections of genes and molecules. It will examine them as physical structures that constantly sense and respond to their surroundings.
That combination of biology, physics, engineering and mathematics is at the center of the FSU-led effort, with researchers hoping that a clearer understanding of the physical changes inside pancreatic tumors will eventually contribute to better ways of detecting, treating and controlling one of the nation’s most deadly cancers.
