Hidden Nuclear Protein Fuels Pancreatic Cancer’s Deadly Aggression

Scientists have uncovered a previously unknown mechanism that helps explain why pancreatic cancer remains one of medicine’s most formidable foes. The discovery centers on a protein that lurks inside the nuclei of cells surrounding tumors, secretly orchestrating the cancer’s notorious resistance to treatment.

Pancreatic cancer, with its dismal five-year survival rate of just 10%, has long confounded researchers seeking effective treatments. Now, a multinational team has identified a surprising new culprit in this lethal dynamic – the Galectin-1 protein operating inside the nuclei of fibroblasts, the cells that form a protective barrier around tumors.

The findings, published April 2 in the Proceedings of the National Academy of Sciences (PNAS), reveal that Galectin-1 doesn’t just work outside cells as previously thought, but also plays a crucial role inside the command centers of fibroblasts.

“The stroma is considered a key component in the aggressive nature of pancreatic cancer, as it interacts with tumor cells, protects them, and hinders the action of drugs,” explains Dr. Pilar Navarro, coordinator of the Cancer Molecular Targets Research Group at the Hospital del Mar Research Institute and IIBB-CSIC-IDIBAPS. “Moreover, stromal cells, particularly fibroblasts, produce substances that support tumor growth and dissemination.”

While scientists previously knew that fibroblasts secrete Galectin-1, this study demonstrates that the protein also operates inside the fibroblasts themselves – specifically in their nuclei – where it controls gene expression in ways that promote cancer growth.

Most striking is the protein’s relationship with KRAS, a gene notorious in pancreatic cancer. KRAS appears in mutated form in tumor cells of 90% of pancreatic cancer patients and drives uncontrolled growth. The researchers discovered that Galectin-1 regulates the normal version of KRAS in fibroblasts.

“Galectin-1 can regulate gene expression in these cells at a highly specific level without altering the DNA sequence, through epigenetic control. One of the genes it regulates is KRAS, which plays a critical role in pancreatic tumors,” Dr. Navarro noted.

The discovery reframes how scientists view the tumor microenvironment in pancreatic cancer. For decades, researchers have understood that the dense tissue surrounding pancreatic tumors – known as the stroma – makes up most of the tumor mass and shields cancer cells from treatment. This new research adds another layer to that understanding by revealing how specific proteins work inside the nuclei of non-cancerous support cells to create an environment where tumors thrive.

Dr. Judith Vinaixa, first author of the study, emphasized the significance of the findings: “We have confirmed the key role of Galectin-1 in the fibroblast cell nucleus, where it regulates the expression of multiple genes critical for cell behavior.”

To reach these conclusions, the team analyzed tissue samples from pancreatic cancer patients and conducted laboratory experiments with human fibroblast cells. When they inhibited both Galectin-1 and KRAS, the fibroblasts stopped supporting tumor growth.

This opens new therapeutic possibilities beyond current approaches. “Until now, efforts have focused on inhibiting Galectin-1 secreted by the stroma surrounding the tumor. Now, we see that we also need to block the protein inside the fibroblast nuclei,” said Dr. Neus Martínez-Bosch, researcher at the Hospital del Mar Research Institute. “We need to find new inhibitors that work inside fibroblasts, not just on the protein they secrete.”

Dr. Gabriel Rabinovich of IBYME (CONICET) and the CaixaResearch Institute points to broader implications: “The next steps will involve exploring therapeutic combinations that inhibit both extracellular and intracellular Galectin-1. This protein also participates in key processes such as blood vessel formation and resistance to immunotherapy. Therefore, this strategy becomes particularly relevant given the multiple antitumoral effects of Galectin-1 inhibition.”

The research represents a significant shift in understanding how the supporting cast of cells around pancreatic tumors contributes to the cancer’s notorious aggressiveness. By targeting both the internal and external functions of Galectin-1, scientists hope to develop more effective approaches to a cancer that has seen little improvement in survival rates over decades.

The study involved researchers from the Hospital del Mar Research Institute, IIBB-CSIC-IDIBAPS, Mayo Clinic, Instituto de Biología y Medicina Experimental (CONICET, Argentina), CaixaResearch Institute, and the Pathology Department at Hospital del Mar, along with researchers from the Cancer Area of CIBER (CIBERONC).