Nuclear Galectin-1 promotes <i>KRAS</i> -dependent activation of pancreatic cancer stellate cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, primarily due to its complex tumor microenvironment (TME), which drives both disease progression and therapy resistance. Understanding the molecular mechanisms governing TME dynamics is essential for developing new treatment strategies for this devastating disease. In this study, we uncover an oncogenic role for Galectin-1 (Gal1), a glycan-binding protein abundantly expressed by activated pancreatic stellate cells (PSCs), a key component of the PDAC TME that orchestrates tumor progression. Our findings reveal that Gal1 expression is elevated in the nucleus of human PSCs in both tissue samples and cultured cell lines. Using chromatin immunoprecipitation followed by sequencing analysis (ChIP-seq), we identify Gal1 occupancy at the promoters of several cancer-associated genes, including <i>KRAS</i>, a pivotal oncogene involved in PDAC pathogenesis. We demonstrate that Gal1 binds to the <i>KRAS</i> promoter, sustaining <i>KRAS</i> expression in PSCs, which, in turn, maintains PSC activation and promotes the secretion of protumorigenic cytokines. Mechanistically, Gal1 is required to preserve histone H3 lysine 4 monomethylation levels and to recruit the histone methyltransferase MLL1 to target promoters. Collectively, our findings define a nuclear function of Gal1 in modulating the transcriptional landscape of cancer-associated genes in PSCs within the PDAC TME, mediated through an epigenetic mechanism. These insights enhance our understanding of PDAC pathology and open potential avenues for therapeutic interventions targeting intracellular Gal1.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-04-02
DOI
https://doi.org/10.1073/pnas.2424051122
Citations
6
Primary Topic
Galectins and Cancer Biology
Type
article
Field-Weighted Citation Impact
4.78

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article

Nuclear Galectin-1 promotes KRAS -dependent activation of pancreatic cancer stellate cells

Mireia Moreno, Noemí Manero‐Rupérez, Joan Gibert, Patricia Santofimia‐Castaño et al.
6 citations
Proceedings of the National Academy of Sciences
Galectins and Cancer Biology
4.78
article

Nuclear Galectin-1 promotes KRAS -dependent activation of pancreatic cancer stellate cells

Mireia Moreno, Noemí Manero‐Rupérez, Joan Gibert, Patricia Santofimia‐Castaño, Gabriel A. Rabinovich, Pilar Chías Navarro, Judith Vinaixa, Federico G. Baudou, Luciana L. Almada, Sandhya Sen, Juan Iovanna, Martín E. Fernández-Zapico, Xiyin Wang, David R. Pease, Neus Martínez‐Bosch, Mar Iglesias, David L. Marks, Renzo E. Vera
article en
6 citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, primarily due to its complex tumor microenvironment (TME), which drives both disease progression and therapy resistance. Understanding the molecular mechanisms governing TME dynamics is essential for developing new treatment strategies for this devastating disease. In this study, we uncover an oncogenic role for Galectin-1 (Gal1), a glycan-binding protein abundantly expressed by activated pancreatic stellate cells (PSCs), a key component of the PDAC TME that orchestrates tumor progression. Our findings reveal that Gal1 expression is elevated in the nucleus of human PSCs in both tissue samples and cultured cell lines. Using chromatin immunoprecipitation followed by sequencing analysis (ChIP-seq), we identify Gal1 occupancy at the promoters of several cancer-associated genes, including <i>KRAS</i>, a pivotal oncogene involved in PDAC pathogenesis. We demonstrate that Gal1 binds to the <i>KRAS</i> promoter, sustaining <i>KRAS</i> expression in PSCs, which, in turn, maintains PSC activation and promotes the secretion of protumorigenic cytokines. Mechanistically, Gal1 is required to preserve histone H3 lysine 4 monomethylation levels and to recruit the histone methyltransferase MLL1 to target promoters. Collectively, our findings define a nuclear function of Gal1 in modulating the transcriptional landscape of cancer-associated genes in PSCs within the PDAC TME, mediated through an epigenetic mechanism. These insights enhance our understanding of PDAC pathology and open potential avenues for therapeutic interventions targeting intracellular Gal1.

Proceedings of the National Academy of SciencesVol. 122(14)
Consejo Superior de Investigaciones Científicas (ES), Inserm (FR), National University of Luján (AR), National Academies of Sciences, Engineering, and Medicine (US), Aix-Marseille Université (FR), Universidad de Buenos Aires (AR), Novel (United States) (US), Institut d'Investigacions Biomèdiques de Barcelona (ES), Cancer Research Center (US), Hospital Del Mar (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Fundación Ciencias Exactas y Naturales (AR), Experimental Medicine and Biology Institute (AR)
Fundación Sales, Fundación René Barón, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 5%
Galectins and Cancer Biology
4.78
DOIOpen Access PDFOpenAlex
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