Scientists have discovered a previously unknown mechanism that helps explain why pancreatic cancer remains one of the most powerful enemies of medicine. The discovery focused on a protein lurking in the nucleus of the surrounding tumor, secretly orchestrating the infamous therapeutic resistance of cancer.
The five-year survival rate for pancreatic cancer is only 10%, which has long troubled researchers seeking effective treatment. Now, a multinational company has identified a surprising new culprit in this deadly dynamic – the galactoconium-1 protein in the fibroblast nucleus, which cells form a protective barrier around the tumor.
The findings, published April 2 in the Proceedings of the National Academy of Sciences (PNAS), show that Galectin-1 not only works outside the cell as previously believed, but also plays a crucial role in the fibroblast command center.
“The matrix is considered a key component of pancreatic cancer’s aggressiveness because it interacts with tumor cells, protects them and hinders the effect of drugs,” explained Dr. Pilar Navarro, coordinator of the Cancer Molecular Target Research Group at the Hospital’s DEL MAR MAR Institute and IIBB-CSIC-CSIC-CSIC-IDIBAPS. “In addition, stromal cells, especially fibroblasts, produce substances that support tumor growth and transmission.”
Although scientists have previously known that fibroblasts secrete galectin-1, the study shows that the protein operates inside the fibroblasts themselves, especially in their nucleus, and it controls gene expression in a way that promotes cancer growth.
Most notably, the relationship between protein and the infamous gene Kras in pancreatic cancer. KRA appears in mutated form in tumor cells in 90% of pancreatic cancer patients and drives uncontrolled growth. The researchers found that Galectin-1 regulates the normal version of KRAS in fibroblasts.
“Galectin-1 can regulate gene expression in these cells through epigenetic controls without changing the DNA sequence. One of the genes it regulates is KRAS, which plays a crucial role in pancreatic tumors,” said Dr. Navarro.
The discovery restructures how scientists view the tumor microenvironment in pancreatic cancer. For decades, researchers have learned that dense tissue around pancreatic tumors, called matrix, constitutes most of the tumor mass and protects the treatment of cancer cells. The new study adds to this understanding by revealing how specific proteins work in the nucleus of noncancerous support cells, thus creating an environment for tumors to reproduce.
Dr. Judith Vinaixa, the first author of the study, emphasized the importance of the discovery: “We have identified the critical role of galectin-1 in the fibroblast nucleus, where it regulates the expression of multiple genes that are critical to cell behavior.”
To draw these conclusions, the team analyzed tissue samples from pancreatic cancer patients and performed laboratory experiments with human fibroblasts. When they inhibit Galectin-1 and Kras, fibroblasts stop supporting tumor growth.
This opens up new therapeutic possibilities for current approaches. “So far, efforts have been focusing on galactoconium 1, which inhibits secretion of the matrix around the tumor. Now, we see that we also need to block proteins in the fibroblast nucleus,” said Dr. Neus Martínez-Bosch, a researcher at the Del Mar Research Institute Hospital. “We need to find new inhibitors that work inside fibroblasts, not just the proteins they secrete.”
Dr. Gabriel Rabinovich and CaixareSearch Institute of Ibyme (Conicet) point to a broader implication: “The next step will involve exploring a combination of therapeutics that inhibit extracellular intracellular galactoconium 1 while also involved in this protein. The protein is also involved in important processes such as angiogenesis and resistance, so this strategy has a variety of effects on immunotherapy inhibition.”
This study represents a significant shift in understanding the cell-supporting castings around pancreatic tumors, which contribute to the infamous competitiveness of cancer. By targeting the internal and external functions of Galectin-1, scientists hope to develop more effective cancer methods, with little improvement in cancer survival.
The study involved the hospitals Del Mar Institute, IIBB-CSIC-IDIBAPS, Mayo Clinic, Biogogíay Medicina Insticent (Conicet, Argentina), the Caixaresearch Institute and the Department of Pathology at the Del Mar Hospital, and researchers from the Ciber Cancer Area (Ciberonc).
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