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

• 成果类型: Article
• 署名作者: Vinaixa, Judith; Martinez-Bosch, Neus; Gibert, Joan; Manero-Ruperez, Noemi; Santofimia-Castano, Patricia; Baudou, Federico G.; Vera, Renzo E.; Pease, David R.; Iglesias, Mar; Sen, Sandhya; Wang, Xiyin; Almada, Luciana L.; Marks, David L.; Moreno, Mireia; Iovanna, Juan L.; Rabinovich, Gabriel A.; Fernandez-Zapico, Martin E.; Navarro, Pilar
• 署名单位: Hospital del Mar Research Institute; Hospital del Mar; Hospital del Mar Research Institute; Hospital del Mar; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); UNICANCER; Institut Paoli-Calmette (IPC); Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Institute of Biology & Experimental Medicine; Universidad Nacional de Lujan; Mayo Clinic; Hospital del Mar Research Institute; Hospital del Mar; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; University of Buenos Aires; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10809
• DOI: 10.1073/pnas.2424051122
• 发表日期: 2025-04-08
• 关键词: extracellular-matrix; t-cells; fibroblasts; ras; proliferation; inhibition; expression; binding; protein; GROWTH

摘要

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 KRAS, a pivotal oncogene involved in PDAC pathogenesis. We demonstrate that Gal1 binds to the KRASpromoter, sustaining KRASexpression 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.