By Patience Moseley, Ph.D.
FSU College of Medicine
Jerome Irianto, Ph.D., assistant professor at the FSU College of Medicine, has secured $2.8 million from the National Cancer Institute to support his lab’s efforts to understand how physical changes in cells contribute to pancreatic cancer progression.
Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is the third-leading cause of cancer death in the United States. The five-year survival rate at detection is 44%, and the prognosis worsens when the cancer spreads beyond the pancreas.
Irianto is channeling his bioengineering and cell biology background to understand how the shape and organization of pancreatic cells change as cancer develops, and whether these physical changes help tumors grow and spread to other parts of the body.
Changes in cell structure and organization are a hallmark of pancreatic cancer progression and are routinely used by pathologists to assess disease stage and progression. Using human-derived pancreatic organoids — miniature 3D models of pancreatic tissue grown in the lab — the Irianto Lab recreated key structural features seen in real patient tumors, from normal pancreatic tissue to advanced cancer.
“When we cultured organoids from normal pancreatic tissue, primary tumors, and metastatic tumors, we immediately noticed that they looked very different,” Irianto said. “Normal organoids have a central hollow space, called a lumen, surrounded by a thin layer of cells, similar to the structure of a normal pancreatic duct in the body. Primary tumor organoids still have a lumen, but the surrounding cell layer becomes much thicker. 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?”
Their biggest question centers on the lumen, the fluid-filled space surrounded by pancreatic epithelial cells. Through years of experimentation, the Irianto Lab has identified ion and water channels as potential drivers of changes in lumen structure. In pancreatic tumor organoids, genes responsible for these channels are expressed at lower levels than in normal pancreatic cells. Their expression decreases even further as tumors progress and spread, suggesting a connection between these channels, changes in lumen structure, and cancer progression.
The lumen depends on the movement of ions and water to maintain its shape and fluid balance. As ions are transported into the lumen, water follows to maintain the proper concentration. The surrounding layer of epithelial cells contains this fluid, creating physical forces that help shape the organoid.
When fewer ion and water channels are present, this delicate balance is disrupted.
“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, Ph.D., 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.
“We have tools that allow us to measure forces between neighboring epithelial cells and forces transmitted to the nuclear envelope surrounding the cell’s DNA. This helps us understand how changes in lumen pressure may ultimately affect cell behavior.”
These physical changes may have important consequences for tumor progression. As ion and water transport decreases, the pressure inside the lumen changes, altering the forces experienced by the surrounding cells.
Under normal cellular conditions, YAP remains outside of the nucleus in an inactive state. When physical forces change or the cell is compressed, YAP is triggered to move into the nucleus in its active state to turn on genes that control cell growth, survival and other behaviors important in cancer. As tumors grow, the tissue around the cells becomes more rigid, perpetuating the influx of YAP into the nucleus and contributing to cancer progression.
The Irianto Lab will investigate whether these changes affect a force-sensitive protein called Yes-associated protein (YAP).
Using gene-editing techniques, Irianto and his team will test how changes in ion and water transport, lumen structure and YAP activity work together to influence pancreatic cancer progression.
Irianto has assembled a multidisciplinary team that includes Driscoll; mathematical modeler Katarzyna Rejniak, Ph.D., of Moffitt Cancer Center; pancreatic cancer biologist Chang-il Hwang, Ph.D., of UC Davis; and pathologist Jose I. Diaz, M.D., of the FSU College of Medicine.
For Irianto, bringing together these different areas of expertise is essential. By combining engineering, cell biology, cancer biology, mathematical modeling, and pathology, the team hopes to uncover aspects of pancreatic cancer that cannot be fully understood by studying genes or biochemical pathways alone. Irianto hopes the NIH-supported work will ultimately reveal new vulnerabilities in pancreatic cancer that could shape future therapeutic strategies.
