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

doi:10.1016/j.celrep.2017.02.037

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 journal › Article › peer-review

84 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 CD95^high-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 language	English (US)
Pages (from-to)	2373-2386
Number of pages	14
Journal	Cell reports
Volume	18
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2017.02.037
State	Published - Mar 7 2017

Funding

We are grateful to Denise Scholten for performing the gene set enrichment analysis and to Drs. Platanias and Horvath for helpful discussions. We would like to thank Dr. Youjia Hua for analyzing the Illumina gene array data, Dr. Yingming Zhao for assessing the labeling efficiency of the cells used in the SILAC experiment, and Angel Alvarez for providing the GSC20 cells. This work was funded by DOD postdoctoral fellowships W81XWH-13-1-0301 (to P.C.), R00CA160638 and ACS127951-RSG-15-025-01-CS (to H.L.), and a Northwestern Memorial Foundation-Lynn Sage Cancer Research Foundation grant R01CA149356, and R35CA197450 (to M.E.P.).

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.02.037

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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

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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.",

keywords = "Fas, STAT1, breast cancer, cancer stem cells, head and neck cancer, type I interferons",

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

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month = mar,

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doi = "10.1016/j.celrep.2017.02.037",

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Qadir, AS, Ceppi, P, Brockway, S, Law, C, Mu, L, Khodarev, NN, Kim, J, Zhao, JC, Putzbach, W, Murmann, AE, Chen, Z, Chen, W, Liu, X, Salomon, AR, Liu, H, Weichselbaum, RR, Yu, J & Peter, ME 2017, 'CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response', Cell reports, vol. 18, no. 10, pp. 2373-2386. https://doi.org/10.1016/j.celrep.2017.02.037

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T1 - CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response

AU - Qadir, Abdul S.

AU - Ceppi, Paolo

AU - Brockway, Sonia

AU - Law, Calvin

AU - Mu, Liang

AU - Khodarev, Nikolai N.

AU - Kim, Jung

AU - Zhao, Jonathan C.

AU - Putzbach, William

AU - Murmann, Andrea E.

AU - Chen, Zhuo

AU - Chen, Wenjing

AU - Liu, Xia

AU - Salomon, Arthur R.

AU - Liu, Huiping

AU - Weichselbaum, Ralph R.

AU - Yu, Jindan

AU - Peter, Marcus E.

PY - 2017/3/7

Y1 - 2017/3/7

N2 - 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.

AB - 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.

KW - Fas

KW - STAT1

KW - breast cancer

KW - cancer stem cells

KW - head and neck cancer

KW - type I interferons

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JF - Cell reports

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ER -

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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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