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Pancreatic cancer stands out as one of the most formidable malignancies, characterized by a low survival rate of merely 10% over five years. A significant factor in its formidable nature is the tumor microenvironment, referred to as the stroma. This stroma constitutes the bulk of the tumor mass and comprises a complex array of proteins and non-tumor cells, including fibroblasts, which play a pivotal role in tumor growth and in enhancing resistance to therapeutic interventions. A recent study conducted by an interdisciplinary team from the Hospital del Mar Research Institute, IIBB-CSIC-IDIBAPS, Mayo Clinic, Instituto de Biología y Medicina Experimental (CONICET, Argentina), and CaixaResearch Institute has uncovered a novel aspect of the Galectin-1 protein’s role in these fibroblasts, particularly its previously unrecognized function within the nuclei of these cells. This groundbreaking research, published in the journal PNAS, sheds new light on the influence of fibroblasts in pancreatic cancer progression.
Dr. Pilar Navarro, who leads the Cancer Molecular Targets Research Group at the Hospital del Mar Research Institute and IIBB-CSIC-IDIBAPS, emphasizes the critical nature of the stroma in pancreatic cancer’s aggressiveness. “The stroma interacts with tumor cells, offers protection, and impedes drug efficacy. Fibroblasts within the stroma generate compounds that nourish tumor growth while also facilitating its spread,” she states. Previously understood to secrete Galectin-1, a protein known to support tumor development, this study reveals that Galectin-1 is also present within the nuclei of fibroblasts, where it plays a crucial role in the regulation of gene expression.
The researchers found that Galectin-1’s presence in fibroblast nuclei activates these cells, enabling them to promote the growth of tumor cells. “Galectin-1 is capable of modulating gene expression in a highly specific manner without changing the DNA sequence itself, through epigenetic mechanisms. For instance, it regulates the KRAS gene, which is a key player in pancreatic tumors,” Dr. Navarro explains. It’s worth noting that mutations in the KRAS gene are present in 90% of pancreatic cancer patients and are considered primary drivers of the disease’s uncontrolled growth and aggressiveness.
Designing new strategies
The research team had previously determined the significant role of Galectin-1 in pancreatic cancer. The newfound understanding of the protein’s functions opens avenues for innovative therapeutic strategies against this cancer type. Dr. Neus Martínez-Bosch, a researcher at the Hospital del Mar Research Institute, asserts, “Previous strategies have primarily aimed at inhibiting the Galectin-1 produced by the surrounding stroma. It’s now evident that we also need to target the protein within the fibroblast nuclei.” She emphasizes the urgency of developing new inhibitors that specifically act within fibroblasts, rather than solely targeting the protein secreted into the tumor environment.
The study was conducted using tissue samples from pancreatic cancer patients to analyze the role of Galectin-1 in fibroblast nuclei. Additionally, the researchers conducted in vitro experiments utilizing human fibroblast cell lines to assess the impact of inhibiting both the Galectin-1 protein and the KRAS gene, which resulted in the deactivation of fibroblasts and ceased their support of tumor cells.
Dr. Judith Vinaixa, the primary author of the study and also a researcher at the Hospital del Mar Research Institute, underscores the significance of the findings: “Our research confirms Galectin-1’s crucial function within the fibroblast nucleus, where it regulates multiple genes vital for cellular behavior.” Dr. Gabriel Rabinovich, associated with IBYME (CONICET) and the CaixaResearch Institute, mentions, “Future efforts will focus on exploring therapeutic combinations that target both extracellular and intracellular Galectin-1. The protein is involved in essential processes like angiogenesis and resistance to immunotherapy, making this approach especially pertinent given Galectin-1’s multifaceted role in tumor biology.”
The study also benefited from collaborations with the Pathology Department at Hospital del Mar and contributions from researchers within the Cancer Area of CIBER (CIBERONC).
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