Overcoming chemotherapy resistance in pancreatic cancer

Pancreatic cancer is known for its aggressive nature and resistance to chemotherapy. Researchers at Stanford University discovered that this resistance is linked to the stiffness and chemical environment of the tissue surrounding cancer cells. Their study, published in Nature Materials, showed that softer tissue makes cancer cells more responsive to chemotherapy, while stiffer tissue makes them resistant.

Sarah Heilshorn, a Stanford professor, explained that these findings offer new insights for developing treatments that could reverse chemoresistance in pancreatic cancer, addressing a significant clinical challenge.

The researchers focused on pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer originating from pancreatic duct cells. They studied how the extracellular matrix (ECM), which becomes stiffer in these cancers, might hinder chemotherapy drugs from reaching cancer cells. Previous treatments targeting this stiff matrix have not been effective in humans.

Led by Sarah Heilshorn and PhD student Bauer LeSavage, they developed a new system using 3D materials that mimic both tumor and healthy pancreatic tissue properties. This allowed them to study how the ECM’s biochemical and mechanical features affect pancreatic cancer cells obtained from patients.

Using their new system, the researchers manipulated cancer cells by activating specific receptors and adjusting their designer matrix’s chemical and physical properties. They discovered that pancreatic cancer develops chemotherapy resistance when exposed to a stiff extracellular matrix with high levels of hyaluronic acid. Hyaluronic acid stiffens the matrix and interacts with cells through the CD44 receptor.

Initially, cancer cells in this environment responded to chemotherapy. However, over time, they adapted by producing proteins on their cell membranes that could quickly expel chemotherapy drugs, rendering them ineffective. The researchers found they could reverse this resistance by transferring cells to a softer matrix, even with high hyaluronic acid levels, or blocking the CD44 receptor, even in a stiff matrix.

Heilshorn said, “We can restore sensitivity to chemotherapy in these cells. This suggests that disrupting stiffness signaling via the CD44 receptor could make pancreatic cancer treatable with standard chemotherapy.”

The finding that pancreatic cancer cells use CD44 receptors to interact with their stiff environment was unexpected, according to Heilshorn. In their study, unlike other cancers, which typically use integrin receptors for similar interactions, pancreatic cancer cells did not utilize integrins.

Heilshorn explained, “We demonstrated that integrin receptors were not involved in our material. This is crucial for designing drugs that could restore chemotherapy sensitivity in patients, as we need to target the right biological pathway.”

Heilshorn and her team continue studying the CD44 receptor and its impact on cancer cells’ resistance mechanisms. Understanding these biological processes could aid drug developers in effectively disrupting chemoresistance. They enhance their cell culture model by incorporating different cell types to simulate tumor environments better and exploring additional mechanical factors beyond stiffness.

This research not only aims to advance treatments for chemoresistance in pancreatic cancer but also underscores the role of the extracellular matrix in cancer progression. Heilshorn emphasizes the importance of using realistic models that mimic patient conditions when testing new therapies, as the matrix surrounding cells influences how they respond to drugs.

Journal reference:

LeSavage, B.L., Zhang, D., Huerta-López, C. et al. Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids. Nature Materials. DOI: 10.1038/s41563-024-01908-x.

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