Study reveals potential target for new pancreatic cancer treatments

Pancreatic cancer

Researchers at Stanford University have revealed new insights related to pancreatic cancer’s resistance to chemotherapy.

In a new paper, the scientists revealed that its resistance is related to both the physical stiffness of the tissue around the cancerous cells and the chemical makeup of the tissue.

The work shows that this resistance can be reversed and reveals potential targets for new pancreatic cancer treatments.

“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 Sarah Heilshorn, Professor of Materials Science and Engineering at Stanford and senior author on the paper. “These results suggest an exciting new direction for future drug development to help overcome chemoresistance, which is a major clinical challenge in pancreatic cancer.”

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

Reversing chemotherapy resistance

The researchers focused their efforts on pancreatic ductal adenocarcinoma, a cancer that starts in the cells lining the ducts of the pancreas and accounts for 90% of pancreatic cancer cases.

In these cancers, the network of materials between the cells, known as the extracellular matrix, becomes notably stiffer.

Heilshorn and PhD student Bauer LeSavage designed three-dimensional materials that mimicked the biochemical and mechanical properties of both pancreatic tumours and healthy pancreas tissues, and used them to culture cells from pancreatic cancer patients.

They found that pancreatic cancer needed two things to become resistant to chemotherapy: a physically stiff extracellular matrix and high amounts of hyaluronic acid – a polymer that helps stiffen the extracellular matrix and interacts with cells through a receptor called CD44.

Initially, the pancreatic cancer cells in a stiff matrix full of hyaluronic acid responded to chemotherapy. But after some time in these conditions, the cancerous cells became resistant to chemotherapy – they made proteins in the cell membrane that could quickly pump out chemotherapy drugs before they could take effect.

The researchers found that they could reverse this development by moving the cells to a softer matrix (even if it was still high in hyaluronic acid) or blocking the CD44 receptor (even if the matrix was still stiff).

“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 signalling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable by normal chemotherapy.”

Diana Spencer, Senior Digital Content Editor, DDW

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