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Cell Rep. 2017 Mar 7;18(10):2373-2386. doi: 10.1016/j.celrep.2017.02.037.

CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.

Author information

1
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
2
Division of Neurological Surgery, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
4
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.
5
Department of Pathology, School of Medicine, Case Western Reserve University and Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
6
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
7
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.
8
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.

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.

KEYWORDS:

Fas; STAT1; breast cancer; cancer stem cells; head and neck cancer; type I interferons

PMID:
28273453
PMCID:
PMC5474321
DOI:
10.1016/j.celrep.2017.02.037
[Indexed for MEDLINE]
Free PMC Article

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