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

Abstract

SUMMARY Stimulation of CD95/Fas drives and maintains cancer stem cells (CSCs). We now report that this involves activation of STAT1, induction of STAT1 regulated genes, and 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 JAK 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 5 primary human cancers. Consequently, we identified Type I IFNs as drivers of cancer stemness. Knockdown or knock-out 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.

STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

“…NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13689-y ARTICLE Importantly, the secretome of chemotherapy-treated cancer cells is double-sided and it may exert protumoral effects in the long term. Chemotherapy triggers IRE1-dependent induction of cytokines to favor breast cancer initiating cell expansion 40 and type I IFN themselves may contribute to this 41 . Chronic activation of type I IFN favors intrinsic resistance to radiotherapy and chemotherapy by inducing specific subsets of Interferon-stimulated genes 42,43 and resistance to immune checkpoint inhibitors by interfering with the PD-1/PD-L1 axis 44 .…”

6mer Seed Toxicity in Viral microRNAs

“…Quantitative real-time PCR. Total RNA extraction, RNA quantification and cDNA preparation were done as previously described (Qadir et al, 2017). 200 ng of RNA in 20 µl of cDNA reaction volume was used to generate cDNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems).…”

The Interactions Between Cancer Stem Cells and the Innate Interferon Signaling Pathway

“…More recently, a robust link between death receptor CD95/Fas, IFN-I-dependent activation of STAT1 and stemness in different cancer types has been described by Qadir et al (160). CD95 is an apoptosis-inducing death receptor, although it can also participate in a variety of tumor promoting activities.…”