Barcelona, 15th April 2025 – Pancreatic cancer remains one of the most lethal malignancies in oncology, with a five-year survival rate lingering at merely 10 percent. This grim prognosis is tightly linked not only to the aggressive nature of the cancer cells themselves but also to the complex and dynamic tumor microenvironment. Known as the stroma, this environment represents the bulk of the tumor mass and is composed of an intricate meshwork of extracellular matrix proteins and non-malignant cells, including immune cells, endothelial cells, and particularly fibroblasts. These fibroblasts, often termed cancer-associated fibroblasts (CAFs), have been recognized as critical facilitators of tumor progression, mediating resistance to therapy and promoting tumor growth through multifaceted interactions. Now, a groundbreaking study spearheaded by an international cohort of researchers from the Hospital del Mar Research Institute, IIBB-CSIC-IDIBAPS, Mayo Clinic, Instituto de Biología y Medicina Experimental (CONICET, Argentina), and the CaixaResearch Institute reveals a previously uncharacterized role of a protein called Galectin-1 within the fibroblast nuclei, providing striking new insights into stromal biology in pancreatic cancer.
For years, Galectin-1, a member of the lectin family known for its carbohydrate-binding properties, has been implicated in tumor progression due to its secretion by stromal fibroblasts, where it promotes immune evasion, angiogenesis, and matrix remodeling. However, until now, the intracellular functions of this molecule, particularly inside fibroblast nuclei, had remained largely unexplored. The recent findings published in the Proceedings of the National Academy of Sciences (PNAS) mark a paradigm shift by demonstrating that nuclear Galectin-1 exerts precise epigenetic control over gene expression programs that drive fibroblast activation, which in turn supports pancreatic tumor progression. This discovery elucidates a novel layer of tumor-stroma crosstalk that may open new therapeutic avenues.
Dr. Pilar Navarro, the coordinator of the Cancer Molecular Targets Research Group at the Hospital del Mar Research Institute and a leading figure in this investigation, explains that the stroma’s notorious role in pancreatic ductal adenocarcinoma (PDAC) aggressiveness hinges on the multifarious functions of fibroblasts. These cells not only secrete factors enhancing tumor cell survival and proliferation but also establish a physical barrier that impedes drug delivery. Importantly, fibroblasts’ secretion of Galectin-1 was known to contribute to these malignant attributes. “Our research reveals that Galectin-1 is not simply secreted into the tumor microenvironment, but it is also localized within the nuclei of stromal fibroblasts, where it functions as a critical regulator of gene expression,” Dr. Navarro remarks, highlighting the dual roles of the protein.
The team conducted comprehensive molecular analyses on pancreatic tumor tissue samples obtained from patients, confirming the nuclear presence of Galectin-1 in stromal fibroblasts in situ. Subsequently, cultured human fibroblast lines were utilized for mechanistic studies, revealing that nuclear Galectin-1 modulates specific gene networks through epigenetic mechanisms, such as histone modification or chromatin remodeling—processes that alter gene expression without changing the underlying DNA sequence. Notably, one of the most significant targets under the regulatory control of nuclear Galectin-1 is the oncogene KRAS, a canonical driver mutated in over 90 percent of PDAC cases and instrumental in promoting cancer cell proliferation and survival.
The regulation of KRAS expression inside fibroblasts is an unprecedented finding, suggesting that fibroblasts may adopt tumor-promoting phenotypes via intracellular signaling pathways converging on KRAS activation. Unlike the mutant version of KRAS in cancer cells, the fibroblast KRAS is wild-type but is upregulated by nuclear Galectin-1, thereby enhancing the supportive role fibroblasts play in tumor development. “This sheds light on a complex, reciprocal relationship wherein fibroblasts not only respond to tumor signals but also actively contribute to sustaining oncogenic programs,” elaborates Dr. Navarro.
These insights pave the way for therapeutic strategies targeting not only the extracellular effects of Galectin-1 but also its newly identified intracellular functions. Dr. Neus Martínez-Bosch, a researcher involved in the project, emphasizes this point, stating, “Previous attempts to inhibit Galectin-1 aimed at blocking the protein secreted by stromal cells. Our results suggest that to effectively disrupt fibroblast-tumor interactions, inhibitors must penetrate the fibroblast nucleus and inhibit Galectin-1’s gene regulatory activities.” Consequently, drug development efforts now face the challenge of identifying molecules capable of entering stromal fibroblasts and precisely modulating nuclear Galectin-1 activity.
To validate the therapeutic potential of targeting nuclear Galectin-1, scientists employed genetic and pharmacological methods to inhibit the protein and KRAS gene expression in cultured fibroblasts. The resultant effects were profound: fibroblast activation was attenuated, leading to a significant decrease in their capacity to sustain malignant behaviors in tumor cells. This evidence strongly supports the concept that disrupting the intracellular axis governed by Galectin-1 may impair the supportive stromal response essential for pancreatic cancer progression.
Dr. Judith Vinaixa, the study’s first author, underscores the breadth of gene expression regulation mediated by nuclear Galectin-1, noting the protein’s influence over multiple gene sets critical for controlling fibroblast behavior. Such multifactorial control mechanisms point to Galectin-1 as a master regulator within the tumor stroma, orchestrating complex epigenetic landscapes that facilitate cancer’s invasive and drug-resistant nature. The diverse roles of Galectin-1 suggest that its inhibition may yield pleiotropic antitumor effects beyond simply reducing fibroblast activation.
Complementing these findings, Dr. Gabriel Rabinovich, a co-investigator from IBYME (CONICET) and the CaixaResearch Institute, highlights the broader implications of Galectin-1 inhibition. Besides its fibroblast-nuclear functions, Galectin-1 contributes to angiogenesis and immune modulation within the tumor milieu, including resistance mechanisms against immunotherapies. Therefore, combined blockade of extracellular and intracellular Galectin-1 activities could synergistically impair tumor growth by both disrupting stromal support and enhancing immune-mediated tumor clearance. This multifaceted approach positions Galectin-1 as a highly promising target in the fight against pancreatic cancer, a disease urgently needing innovative therapeutic interventions.
The collaborative nature of this study, incorporating pathology experts from Hospital del Mar and cancer research specialists from CIBERONC, underscores the multidisciplinary effort required to unravel the complexities of the pancreatic tumor microenvironment. Their joint expertise facilitated the integration of histological evaluation with molecular biology and epigenetics, strengthening the validity and clinical relevance of the findings.
As the field moves forward, future research will inevitably focus on drug discovery tailored to inhibit nuclear Galectin-1, optimizing delivery systems to achieve efficient intracellular targeting in fibroblasts. Moreover, combination therapies that simultaneously target extracellular Galectin-1 and other tumor-promoting pathways could revolutionize treatment paradigms for pancreatic cancer. These innovative approaches stand to overcome one of the most formidable hurdles in oncology by dismantling the protective tumor stroma and restoring therapeutic efficacy.
Ultimately, this landmark study redefines our understanding of the pancreatic tumor microenvironment by spotlighting a novel nuclear function of Galectin-1 within stromal fibroblasts. The findings not only deepen the biological comprehension of stromal-tumor interactions but also open promising new pathways for the development of targeted therapies, giving hope to patients suffering from one of the deadliest cancers known today.
Subject of Research: Nuclear functions of Galectin-1 in pancreatic cancer-associated fibroblasts and its role in tumor progression
Article Title: Nuclear Galectin-1 promotes KRAS-dependent activation of pancreatic cancer stellate cells
News Publication Date: 15th April 2025
Web References:
https://doi.org/10.1073/pnas.2424051122
References:
Vinaixa J, Martínez-Bosch N, Gibert J, Manero-Rupérez N, Santofimia-Castaño P, Baudou FG, Vera RE, Pease DR, Iglesias M, Sen S, Wang X, Almada LL, Marks DL, Moreno M, Iovanna JL, Rabinovich GA, Fernandez-Zapico ME, Navarro P. Nuclear Galectin-1 promotes KRAS-dependent activation of pancreatic cancer stellate cells. Proc Natl Acad Sci U S A. 2025 Apr 8;122(14):e2424051122. doi: 10.1073/pnas.2424051122. Epub 2025 Apr 2. PMID: 40172967.
Keywords: Pancreatic cancer, tumor microenvironment, stroma, fibroblasts, Galectin-1, nuclear proteins, epigenetic regulation, KRAS gene, cancer-associated fibroblasts, tumor progression, drug resistance, immunotherapy resistance
