Scientists Discover Method to Reverse Chemo Resistance in Pancreatic Cancer

Pancreatic cancer is a particularly aggressive disease, notoriously difficult to treat primarily due to its resistance to chemotherapy. Recent research has shed light on the reasons behind this resistance and has proposed potential methods to overcome it.

Researchers have discovered that the physical stiffness of the tissue surrounding pancreatic cancer cells plays a significant role in reducing the effectiveness of chemotherapy. This breakthrough, reported on July 4 in the journal Nature Materials, indicates that stiffer tissues render the cancer cells less responsive to treatment, while softer tissues make them more susceptible to chemotherapy.

Sarah Heilshorn, a professor of materials science and engineering at Stanford University, led the study. She explained, "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." This discovery opens new pathways for drug development aimed at mitigating chemoresistance, a significant clinical challenge in treating pancreatic cancer.

The research primarily focused on pancreatic ductal adenocarcinoma, which accounts for 90% of pancreatic cancer cases. This form of cancer originates in the cells lining the ducts of the pancreas. In this type of cancer, the surrounding tissue becomes significantly stiffer, creating a physical barrier that prevents chemotherapy from effectively reaching the cancer cells.

To better understand this phenomenon, the researchers engineered tissue in the lab that replicated the properties of both pancreatic tumors and healthy pancreatic tissues. They then used this engineered tissue to culture cells taken from pancreatic cancer patients.

"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 noted. The study revealed that both the stiffness of the tissue and the presence of high levels of hyaluronic acid contributed to the cancer's resistance to chemotherapy. Hyaluronic acid helps stiffen the tissue by interacting with cellular tissue through a receptor called CD44.

The researchers found that by blocking the CD44 receptor, they could soften the tissue and make the cancer cells 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 chain of events activated within cancerous cells. They are also working on enhancing their cell culture model to better predict how chemotherapy and other cancer therapies 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 innovative approach to understanding and potentially overcoming chemoresistance in pancreatic cancer holds promise for developing more effective treatments and improving the prognosis for patients afflicted with this challenging disease.