One of the keys to the aggressiveness of pancreatic cancer has been found.
A team led by Catalan researchers has identified a potential target for treating this highly lethal tumor.
BarcelonaPancreatic cancer survival rates five years after detection are among the lowest, at just 10%. Its aggressiveness is due, in part, to late diagnosis, but also to the dome of proteins and cells that protects the tumor, the so-called stroma. Now, a study led by Catalan research centers has identified a new key role played by the Galectin-1 protein in the nucleus of cells surrounding the tumor, hiding it from the action of the immune system and increasing its resistance to drugs, since the medications are unable to cross the barrier.
This function had not been described until now. Although it was known that fibroblasts—a type of cell that contributes to the formation of connective tissue, which provides connection, support, and separation between other types of tissue in the body—secreted Galectin-1, a substance that promotes tumor growth, extracellularly, it has now been shown that the molecule is also found in the nucleus of these cells.
In the research, published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), the second most cited scientific journal in the world, the Hospital del Mar Research Institute, the Barcelona Biomedical Research Institute (IIBB-CSIC-IDIBAPS), and the CaixaResearch Institute participated in the review. They did so in collaboration with the Mayo Clinic and the Institute of Biology and Experimental Medicine (IBYME) in Argentina. The results pave the way for the search for new therapeutic strategies that inhibit the action of this protein inside the cells that protect the tumor.
Pilar Navarro, coordinator of the New Molecular Targets of Cancer Research Group at the Hospital del Mar Research Institute and IIBB-CSIC-IDIBAPS, explains that the stroma is considered "a key element in the aggressive biology of cancer that impedes the action of drugs." "Stroma cells, particularly fibroblasts, produce substances that promote tumor growth and facilitate its growth and spread," she adds.
Furthermore, researchers have discovered how Galectin-1 has the ability to regulate gene expression in these cells at a very specific level without modifying the DNA sequence through epigenetic control. One of the genes it targets is KRAS, which is found in the tumor cells of 90% of patients. When mutated, it allows the tumor to expand indefinitely and, for this reason, is considered one of the main causes of uncontrolled growth and the aggressiveness of pancreatic cancer.
New therapeutic strategies
This team had already identified in previous studies the prominent role of Galectin-1 in pancreatic cancer, but the newly discovered functions now open the door to designing new strategies to attack this type of tumor. "Until now, efforts have focused on inhibiting Galectin-1 secreted by the stroma surrounding the tumor. Now, however, we see that the protein present in the nucleus of fibroblasts must also be blocked," says Neus Martínez-Bosch, a researcher at the Hospital del Mar Research Institute. "We need to find new inhibitors that act within fibroblasts and not just on the protein they secrete," she emphasizes.
In the study, the researchers worked with samples from patients with pancreatic cancer, which allowed them to analyze the presence and function of Galectin-1 in the nucleus of fibroblasts. In addition, they conducted experiments. in vitro with human fibroblast cell lines to investigate the effects of inhibiting both the protein and the KRAS gene, and the subsequent deactivation of these cells. Judith Vinaixa, a researcher at the Hospital del Mar research center and first author of the study, highlights the relevance of these results: "We have verified the importance of the role of Galectin-1 in the cell nucleus of fibroblasts, where it regulates the expression of multiple genes important for the cell."
Gabriel Rabinovich, a researcher at IBYME (CONICET) and the CaixaResearch Institute, explains that the next steps will now be "to explore therapeutic combinations that allow the inhibition of both extracellular and intracellular Galectin-1." "This protein is also involved in key tumor processes such as blood vessel formation and resistance to immunotherapy. Therefore, this strategy takes on particular importance considering the multiple antitumor capacity of inhibiting this protein," he concludes.
