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

A.S. Qadir; P. Ceppi; S. Brockway; C. Law; L. Mu; N.N. Khodarev; J. Kim; J.C. Zhao; W. Putzbach; A.E. Murmann; Z. Chen; W. Chen; X. Liu; A.R. Salomon; H. Liu; R.R. Weichselbaum; J. Yu; M.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

A.S. Qadir, P. Ceppi, S. Brockway, C. Law, L. Mu, N.N. Khodarev, J. Kim, J.C. Zhao, W. Putzbach, A.E. Murmann, Z. Chen, W. Chen, X. Liu, A.R. Salomon, H. Liu, R.R. Weichselbaum, J. Yu, M.E. Peter

Research output: Contribution to journal › Journal article › Research › peer-review

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
Journal	Cell Reports
Volume	18
Issue number	10
Pages (from-to)	2373-2386
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2017.02.037
Publication status	Published - 2017
Externally published	Yes

Keywords

Fas
STAT1
breast cancer
cancer stem cells
head and neck cancer
type I interferons
Up-Regulation
Caspase 3/metabolism
Phosphorylation
STAT1 Transcription Factor/metabolism
Signal Transduction
Down-Regulation
Humans
Gene Expression Regulation, Neoplastic
Neoplastic Stem Cells/metabolism
Gene Knockout Techniques
fas Receptor/metabolism
RNA, Small Interfering/metabolism
Cell Line, Tumor
Isotope Labeling
Female
Interferon Type I/metabolism
Breast Neoplasms/genetics

Documents & Links

10.1016/j.celrep.2017.02.037

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

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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 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.",

keywords = "Fas, STAT1, breast cancer, cancer stem cells, head and neck cancer, type I interferons, Up-Regulation, Caspase 3/metabolism, Phosphorylation, STAT1 Transcription Factor/metabolism, Signal Transduction, Down-Regulation, Humans, Gene Expression Regulation, Neoplastic, Neoplastic Stem Cells/metabolism, Gene Knockout Techniques, fas Receptor/metabolism, RNA, Small Interfering/metabolism, Cell Line, Tumor, Isotope Labeling, Female, Interferon Type I/metabolism, Breast Neoplasms/genetics",

author = "A.S. Qadir and P. Ceppi and S. Brockway and C. Law and L. Mu and N.N. Khodarev and J. Kim and J.C. Zhao and W. Putzbach and A.E. Murmann and Z. Chen and W. Chen and X. Liu and A.R. Salomon and H. Liu and R.R. Weichselbaum and J. Yu and M.E. Peter",

year = "2017",

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

language = "English",

volume = "18",

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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

TY - JOUR

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

AU - Qadir, A.S.

AU - Ceppi, P.

AU - Brockway, S.

AU - Law, C.

AU - Mu, L.

AU - Khodarev, N.N.

AU - Kim, J.

AU - Zhao, J.C.

AU - Putzbach, W.

AU - Murmann, A.E.

AU - Chen, Z.

AU - Chen, W.

AU - Liu, X.

AU - Salomon, A.R.

AU - Liu, H.

AU - Weichselbaum, R.R.

AU - Yu, J.

AU - Peter, M.E.

PY - 2017

Y1 - 2017

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 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.

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 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.

KW - Fas

KW - STAT1

KW - breast cancer

KW - cancer stem cells

KW - head and neck cancer

KW - type I interferons

KW - Up-Regulation

KW - Caspase 3/metabolism

KW - Phosphorylation

KW - STAT1 Transcription Factor/metabolism

KW - Signal Transduction

KW - Down-Regulation

KW - Humans

KW - Gene Expression Regulation, Neoplastic

KW - Neoplastic Stem Cells/metabolism

KW - Gene Knockout Techniques

KW - fas Receptor/metabolism

KW - RNA, Small Interfering/metabolism

KW - Cell Line, Tumor

KW - Isotope Labeling

KW - Female

KW - Interferon Type I/metabolism

KW - Breast Neoplasms/genetics

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85014578201&partnerID=MN8TOARS

U2 - 10.1016/j.celrep.2017.02.037

DO - 10.1016/j.celrep.2017.02.037

M3 - Journal article

C2 - 28273453

SN - 2211-1247

VL - 18

SP - 2373

EP - 2386

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

Abstract

Keywords

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