Pancreatic cancer remains one of the most aggressive and difficult-to-treat cancers, largely due to its resistance to chemotherapy. Researchers now believe they have uncovered the reason behind this resistance and a potential way to overcome it.

A study published on July 4 in the journal Nature Materials revealed that the physical stiffness of the tissue surrounding pancreatic cancer cells hinders the effectiveness of chemotherapy. This discovery was made by a team led by Sarah Heilshorn, a professor of materials science and engineering at Stanford University.

"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," Heilshorn stated in a news release. "These results suggest an exciting new direction for future drug development to help overcome chemoresistance, which is a major clinical challenge in pancreatic cancer."

The research focused on pancreatic ductal adenocarcinoma, which accounts for 90% of pancreatic cancer cases. This type of cancer originates in the cells lining the ducts of the pancreas and is characterized by notably stiffer surrounding tissue. This stiffness acts as a barrier, preventing chemotherapy from effectively reaching the cancer cells.

To better understand this phenomenon, the researchers created lab-designed tissue that mimicked the properties of both pancreatic tumors and healthy pancreas tissues. They then cultured cells from pancreatic cancer patients within this engineered tissue.

"We created a designer matrix that would allow us to test the idea that these cancerous cells might be responding to the chemical signals and mechanical properties in the matrix around them," Heilshorn explained.

Their findings identified two key factors contributing to the chemoresistance: stiffer tissue and high levels of hyaluronic acid, a substance that contributes to tissue stiffness. Hyaluronic acid interacts with cellular tissue through a receptor called CD44. The researchers discovered that by blocking the CD44 receptor, they could make the tissue softer and more responsive to chemotherapy.

"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 research team continues to explore the CD44 receptor and the subsequent cellular events triggered upon its activation in cancer cells. Additionally, they are working on refining their cell culture model to better predict how chemotherapy and other treatments will perform in individual patients.

"When we design chemotherapies, we should be testing our cultures in matrices that are relevant to a patient," Heilshorn emphasized. "Because it matters – the way cells respond to drugs depends on the matrix that’s around them."

This groundbreaking study opens new avenues for developing treatments that can overcome the formidable barrier of chemoresistance in pancreatic cancer, offering hope for more effective therapies in the future.