California [USA], due in part to its frequent resistance to treatment, pancreatic cancer is a particularly aggressive and difficult-to-treat malignancy. According to a Stanford study, this resistance is related to the chemical composition of the surrounding tissue, as well as the physical rigidity of the tissue around the malignant cells.
His research demonstrates that this resistance can be overcome and identifies potential targets for novel treatments for pancreatic cancer. It was published in Nature Materials.
"We found that stiffer tissue can make pancreatic cancer cells resistant to chemotherapy, while softer tissue makes cancer cells more responsive to chemotherapy," said Sarah Heilshorn, professor of science and engineering. of materials at Stanford and lead author of the article. "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 researchers focused their efforts on pancreatic ductal adenocarcinoma, a cancer that begins in the cells that line the ducts of the pancreas and accounts for 90% of pancreatic cancer cases. In these cancers, the network of materials between cells, known as the extracellular matrix, becomes noticeably stiffer. Scientists have theorized that this rigid material acts as a physical block, preventing chemotherapy drugs from reaching cancer cells, but treatments based on this idea have not been effective in humans.
Heilshorn worked with doctoral student Bauer LeSavage, lead author of the paper, to develop a new system to study these changes in the extracellular matrix and better understand their impact on pancreatic cancer cells. They designed three-dimensional materials that mimicked the biochemical and mechanical properties of both pancreatic tumors and healthy pancreatic tissues, and used them to grow cells from pancreatic cancer patients, which they received from Calvin Kuo, the Maureen Lyles D'Ambrogio Professor at Stanford. Medicine. .
"We created a designer matrix that would allow us to test the idea that these cancer cells could be responding to chemical signals and mechanical properties of the matrix around them," Heilshorn said. Using their new system, the researchers selectively activated certain types of receptors on cancer cells and adjusted the chemical and physical properties of their design matrix. They found that pancreatic cancer needed two things to become resistant to chemotherapy: a physically rigid 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, pancreatic cancer cells in a rigid matrix filled with hyaluronic acid responded to chemotherapy. But after some time in these conditions, the cancer cells became resistant to chemotherapy: they produced proteins in the cell membrane that could rapidly pump out the 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 by blocking the CD44 receptor (even if the matrix was still stiff).
"We can revert the cells to a state where they are sensitive to chemotherapy," Heilshorn said. "This suggests that if we can disrupt the stiffness signaling that occurs through the CD44 receptor, we could make patients' pancreatic cancer treatable with normal chemotherapy." The discovery that pancreatic cancer cells interact with the matrix surrounding them through the CD44 receptors was a surprise, Heilshorn said. Other cancers can be affected by the mechanical properties of the extracellular matrix, but these interactions usually work through a different class of receptors called integrins.
"We showed that pancreatic cancer cells were not actually using integrin receptors in our materials," Heilshorn said. "That's important, because if you want to design a drug to resensitize the patient's cells to chemotherapy, you need to know which biological pathway to interfere with."
Heilshorn and his colleagues continue to investigate the CD44 receptor and the chain of events that follows after it is activated in a cancer cell. The more they can reveal about the biological mechanisms that lead to chemoresistance, the easier it will be for drug developers to find a way to disrupt the process. The researchers are also working to improve their cell culture model, adding new cell types to mimic improving the environment around a tumor and modifying it to investigate other mechanical properties beyond stiffness. In addition to opening new avenues for treating chemoresistance in pancreatic cancer, the researchers hope this work will highlight the potential role of the extracellular matrix in cancer progression and the importance of using realistic models to find treatments.
"When we design chemotherapies, we should test our cultures in matrices that are relevant to a patient," Heilshorn said. "Because it matters: The way cells respond to drugs depends on the matrix that surrounds them."
His research demonstrates that this resistance can be overcome and identifies potential targets for novel treatments for pancreatic cancer. It was published in Nature Materials.
"We found that stiffer tissue can make pancreatic cancer cells resistant to chemotherapy, while softer tissue makes cancer cells more responsive to chemotherapy," said Sarah Heilshorn, professor of science and engineering. of materials at Stanford and lead author of the article. "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 researchers focused their efforts on pancreatic ductal adenocarcinoma, a cancer that begins in the cells that line the ducts of the pancreas and accounts for 90% of pancreatic cancer cases. In these cancers, the network of materials between cells, known as the extracellular matrix, becomes noticeably stiffer. Scientists have theorized that this rigid material acts as a physical block, preventing chemotherapy drugs from reaching cancer cells, but treatments based on this idea have not been effective in humans.
Heilshorn worked with doctoral student Bauer LeSavage, lead author of the paper, to develop a new system to study these changes in the extracellular matrix and better understand their impact on pancreatic cancer cells. They designed three-dimensional materials that mimicked the biochemical and mechanical properties of both pancreatic tumors and healthy pancreatic tissues, and used them to grow cells from pancreatic cancer patients, which they received from Calvin Kuo, the Maureen Lyles D'Ambrogio Professor at Stanford. Medicine. .
"We created a designer matrix that would allow us to test the idea that these cancer cells could be responding to chemical signals and mechanical properties of the matrix around them," Heilshorn said. Using their new system, the researchers selectively activated certain types of receptors on cancer cells and adjusted the chemical and physical properties of their design matrix. They found that pancreatic cancer needed two things to become resistant to chemotherapy: a physically rigid 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, pancreatic cancer cells in a rigid matrix filled with hyaluronic acid responded to chemotherapy. But after some time in these conditions, the cancer cells became resistant to chemotherapy: they produced proteins in the cell membrane that could rapidly pump out the 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 by blocking the CD44 receptor (even if the matrix was still stiff).
"We can revert the cells to a state where they are sensitive to chemotherapy," Heilshorn said. "This suggests that if we can disrupt the stiffness signaling that occurs through the CD44 receptor, we could make patients' pancreatic cancer treatable with normal chemotherapy." The discovery that pancreatic cancer cells interact with the matrix surrounding them through the CD44 receptors was a surprise, Heilshorn said. Other cancers can be affected by the mechanical properties of the extracellular matrix, but these interactions usually work through a different class of receptors called integrins.
"We showed that pancreatic cancer cells were not actually using integrin receptors in our materials," Heilshorn said. "That's important, because if you want to design a drug to resensitize the patient's cells to chemotherapy, you need to know which biological pathway to interfere with."
Heilshorn and his colleagues continue to investigate the CD44 receptor and the chain of events that follows after it is activated in a cancer cell. The more they can reveal about the biological mechanisms that lead to chemoresistance, the easier it will be for drug developers to find a way to disrupt the process. The researchers are also working to improve their cell culture model, adding new cell types to mimic improving the environment around a tumor and modifying it to investigate other mechanical properties beyond stiffness. In addition to opening new avenues for treating chemoresistance in pancreatic cancer, the researchers hope this work will highlight the potential role of the extracellular matrix in cancer progression and the importance of using realistic models to find treatments.
"When we design chemotherapies, we should test our cultures in matrices that are relevant to a patient," Heilshorn said. "Because it matters: The way cells respond to drugs depends on the matrix that surrounds them."
