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

Abdul S. Qadir, Paolo Ceppi, Sonia Brockway, Calvin Law, Liang Mu, Nikolai N. Khodarev, Jung Kim, Jonathan C. Zhao, William Putzbach, Andrea E. Murmann, Zhuo Chen, Wenjing Chen, Xia Liu, Arthur R. Salomon, Huiping Liu, Ralph R. Weichselbaum, Jindan Yu, Marcus E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2373-2386
Number of pages14
JournalCell reports
Volume18
Issue number10
DOIs
StatePublished - Mar 7 2017

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Qadir, A. S., Ceppi, P., Brockway, S., Law, C., Mu, L., Khodarev, N. N., Kim, J., Zhao, J. C., Putzbach, W., Murmann, A. E., Chen, Z., Chen, W., Liu, X., Salomon, A. R., Liu, H., Weichselbaum, R. R., Yu, J., & Peter, M. E. (2017). CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response. Cell reports, 18(10), 2373-2386. https://doi.org/10.1016/j.celrep.2017.02.037