title: CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.
abstract: Stimulation of CD95/Fas drives and maintains cancer stem cells (CSCs). We now report that this involves activation of signal transducer and activator of transcription 1 (STAT1) and induction of STAT1-regulated genes and that this process is inhibited by active caspases. STAT1 is enriched in CSCs in cancer cell lines, patient-derived human breast cancer, and CD95high-expressing glioblastoma neurospheres. CD95 stimulation of cancer cells induced secretion of type I interferons (IFNs) that bind to type I IFN receptors, resulting in activation of Janus-activated kinases, activation of STAT1, and induction of a number of STAT1-regulated genes that are part of a gene signature recently linked to therapy resistance in five primary human cancers. Consequently, we identified type I IFNs as drivers of cancer stemness. Knockdown or knockout of STAT1 resulted in a strongly reduced ability of CD95L or type I IFN to increase cancer stemness. This identifies STAT1 as a key regulator of the CSC-inducing activity of CD95.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Abdul S
authors.initials: AS
authors.lastname: Qadir
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ceppi
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Brockway
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Law
authors.affiliation: Division of Neurological Surgery, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Mu
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Khodarev
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Zhao
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: William
authors.initials: W
authors.lastname: Putzbach
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Murmann
authors.affiliation: Center for Cancer Research and Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI 02903, USA; Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University and Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Cancer Research and Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI 02903, USA; Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Salomon
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Pathology, School of Medicine, Case Western Reserve University and Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: m-peter@northwestern.edu.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007553:Isotope Labeling; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; D007370:Interferon Type I; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D019014:fas Receptor; D053148:Caspase 3
keywords: Fas; STAT1; breast cancer; cancer stem cells; head and neck cancer; type I interferons