title: ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells.
abstract: Cancer stem cells (CSC) are thought to play a major role in the development and metastatic progression of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Likewise, the tumor microenvironment contributes critical support in this setting, including from tumor stromal cells and tumor-associated macrophages (TAM) that contribute structural and paracrine-mediated supports, respectively. Here, we show that TAMs secrete the IFN-stimulated factor ISG15, which enhances CSC phenotypes in PDAC in vitro and in vivo. ISG15 was preferentially and highly expressed by TAM present in primary PDAC tumors resected from patients. ISG15 was secreted by macrophages in response to secretion of IFNβ by CSC, thereby reinforcing CSC self-renewal, invasive capacity, and tumorigenic potential. Overall, our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression.
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma, Madrid, Spain. bruno.sainz@uam.es susana.guerra@uam.es.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martín
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marianthi
authors.initials: M
authors.lastname: Tatari
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.affiliation: Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma, Madrid, Spain. bruno.sainz@uam.es susana.guerra@uam.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Guerra
mesh_terms: D014408:Biomarkers, Tumor; D063646:Carcinogenesis / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment / Q000235:genetics; D014452:Ubiquitins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D014452:Ubiquitins; C074034:ISG15 protein, human