What will you learn?
1. How can the discovery by Stanford University scientists reverse chemotherapy resistance in pancreatic cancer?
2. What did scientists focus on when studying pancreatic ductal adenocarcinoma?
3. What two things are needed for pancreatic cancer cells to become resistant to chemotherapy?
4. What was the surprise regarding CD44 receptors in pancreatic cancer cells?
5. What further steps do scientists plan in their research on chemotherapy resistance in pancreatic cancer?
The Power of the Extracellular Matrix
The researchers focused on pancreatic ductal adenocarcinoma, which accounts for 90% of pancreatic cancer cases. In these cancers, the network of materials between cells, known as the extracellular matrix, becomes notably stiffer. Scientists have hypothesized that this stiff material acts as a physical barrier, preventing chemotherapy drugs from reaching cancerous cells. However, treatments based on this idea have not been effective in humans.
Sarah Heilshorn, a professor of materials science and engineering at Stanford, worked with Ph.D. student Bauer LeSavage to develop a new system to study these changes in the extracellular matrix and better understand their impact on pancreatic cancer cells. The team designed three-dimensional materials that mimicked the biochemical and mechanical properties of both pancreatic tumors and healthy pancreatic tissues, and used them to culture cells from pancreatic cancer patients.
Research Findings
The new system allowed the researchers to selectively activate certain types of receptors in the cancer cells and adjust the chemical and physical properties of the matrix. They discovered that pancreatic cancer cells need two things to become resistant to chemotherapy: a stiff extracellular matrix and high amounts of hyaluronic acid, a polymer that helps stiffen the matrix and interacts with cells through a receptor called CD44.
Initially, pancreatic cancer cells in a stiff matrix with high hyaluronic acid levels responded to chemotherapy. However, over time in these conditions, the cancer cells became resistant to chemotherapy by producing 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 process by moving the cells to a softer matrix or blocking the CD44 receptor.
Steps Toward Treatment
The discovery that pancreatic cancer cells interact with the stiff matrix through CD44 receptors was surprising. Other cancers can be affected by the mechanical properties of the extracellular matrix, but these interactions typically occur through a different class of receptors called integrins. Heilshorn’s research shows that pancreatic cancer cells do not use integrin receptors in their materials, which is important for designing drugs to resensitize patient cells to chemotherapy.
The researchers continue to investigate the CD44 receptor and the chain of events that follow its activation in a cancer cell. The more they learn about the biological mechanisms leading to chemoresistance, the easier it will be for drug developers to find ways to disrupt the process.
The team is also working to improve their cell culture model by adding new types of cells to better mimic the environment around a tumor and by investigating other mechanical properties beyond stiffness. In addition to opening new avenues for treating chemoresistance in pancreatic cancer, the researchers hope their work will highlight the potential role of the extracellular matrix in cancer progression and the importance of using realistic models to find treatments.
Source: Stanford University
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