Investigators at Stanford University have discovered the role of cell stiffness and the chemical makeup of pancreatic cancer tissue has in its resistance to chemotherapy. The research, published in Nature Materials, suggests that treatment resistance can be reversed and has uncovered new potential therapeutic targets to do this.
“We found that stiffer tissue can cause pancreatic cancer cells to become resistant to chemotherapy, while softer tissue made the cancer cells more responsive to chemotherapy,” said senior author Sarah Heilshorn, a professor of materials science and engineering at Stanford. “These results suggest an exciting new direction for future drug development to help overcome chemoresistance, which is a major clinical challenge in pancreatic cancer.”
For their work, the Stanford team focused on the most common form of the disease pancreatic ductal adenocarcinoma, which accounts for about 90% of all cases. This form takes shape in the cells lining the ducts of the pancreas, during which time the cells in the extracellular matrix becomes notably stiffer. Previous studies of pancreatic cancer treatment resistance have theorized that this stiffness effectively serves as a physical barrier that prevents chemotherapy from reaching cancer cells. To date, attempts to develop treatments based on this notion have not been successful.
To get a more detailed understanding of how the changes of the extracellular matrix affect cancerous cells, Heilshorn and lead author Bauer LeSavage designed three-dimensional materials to recreate the mechanical and biochemical properties of both healthy pancreas tissues and pancreatic tumors.
They then used these to culture pancreatic cancer cells that had been collected from patients and manipulated the chemical and physical properties of their cellular matrix, while also activates receptors on the cancerous cells. From this, they discovered pancreatic cancer needed both a stiff extracellular matrix and high levels of hyaluronic acid. This acid helps to stiffen the extracellular matrix via interaction with cells through the CD44 receptor.
While the pancreatic cancer cells used in their experiments with a stiff extracellular matrix and high levels of hyaluronic acid initially responded to chemotherapy, over time they became resistant by making proteins in the cell membrane that could quickly push out the drugs before they were able to affect the cancerous cells. When the investigators moved the cells to a matrix that was softer, they could reverse the development of resistance—even if they still had high levels of hyaluronic acid. They also achieved this by blocking the CD44 receptor even in a stiff matrix.
“We can revert the cells back to a state where they are sensitive to chemotherapy,” Heilshorn said. “This suggests that if we can disrupt the stiffness signaling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable by normal chemotherapy.”
The team noted that the discovery of the interaction of the pancreatic cells with a stiff matrix surrounding them through CD44 receptors was an unexpected finding. Other cancers that are affected by the mechanical properties of the extracellular matrix typically work through a class of receptors called integrins. This a significant findings since resensitizing patients to chemotherapy requires knowing exactly what pathway to disrupt.
Continuing research by the team seeks to further understand what happens in the cancerous cells after the CD44 receptor is activated. They are also continuing to refine their cell culture model to more closely resemble the tumor and the tumor environment with a goal of a deeper understanding of the mechanics of cells other than stiffness.
