TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Biroccio, Annamaria; Cherfils‐Vicini, Julien; Augereau, Adeline; Pinte, Sébastien; Bauwens, Serge; Ye, Jing; Simonet, Thomas; Horard, Béatrice; Jamet, Karine; Cervera, Ludovic; Méndez-Bermúdez, Aarón; Poncet, Delphine; Grataroli, Renée; Rodenbeeke, Claire T Kint De; Salvati, Erica; Rizzo, Angela; Zizza, Pasquale; Ricoul, Michelle; Cognet, Céline; Kuilman, Thomas; Duret, Helene; Lépinasse, Florian; Marvel, Jacqueline; Verhoeyen, Els; Cosset, François‐Loïc; Peeper, Daniel S.; Smyth, Mark J.; Londoño-Vallejo, Arturo; Sabatier, Laure; Picco, Vincent; Pagès, Gilles; Scoazec, Jean Yves; Stoppacciaro, Antonella; Leonetti, Carlo; Vivier, Éric; Gilson, Éric

doi:10.1038/ncb2774

Cited by 105 publications

(136 citation statements)

References 61 publications

(60 reference statements)

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“…Telomere uncapping was found to be associated with cellular senescence and inflammation in human arteries (55). Furthermore, malignant cells with elevated TRF2 levels had a decrease in natural killer (NK) cell infiltration in the tumor microenvironment (56). These findings suggest that telomeres contribute directly or indirectly to inflammatory signaling.…”

Section: Discussionmentioning

confidence: 71%

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Wang

Deng

Dahmane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Telomeric repeat-containing RNA (TERRA) has been identified as a telomere-associated regulator of chromosome end protection. Here, we report that TERRA can also be found in extracellular fractions that stimulate innate immune signaling. We identified extracellular forms of TERRA in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. Cell-free TERRA (cfTERRA) could be isolated from the exosome fractions derived from human lymphoblastoid cell line (LCL) culture media. cfTERRA is a shorter form (∼200 nt) of cellular TERRA and copurifies with CD63-and CD83-positive exosome vesicles that could be visualized by cyro-electron microscopy. These fractions were also enriched for histone proteins that physically associate with TERRA in extracellular ChIP assays. Incubation of cfTERRAcontaining exosomes with peripheral blood mononuclear cells stimulated transcription of several inflammatory cytokine genes, including TNFα, IL6, and C-X-C chemokine 10 (CXCL10) Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. These findings imply a previously unidentified extrinsic function for TERRA and a mechanism of communication between telomeres and innate immune signals in tissue and tumor microenvironments.TERRA | telomere | exosome | innate immunity | cytokine

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Section: Discussionmentioning

confidence: 71%

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Wang

Deng

Dahmane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It remains unclear whether the levels of heparin necessary for metastasis inhibition in mouse models are achievable in human patients without prohibitive anticoagulation [66]. Heparin, HSPGs, and their modifying enzymes can have immunomodulatory effects that alter tumor growth and metastasis [76, 77]. Though not discussed here, the effects of heparin and HSPGs on tumor immunology represent an important area for future exploration.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate signaling in cancer

Knelson

Nee

Blobe

2014

Trends in Biochemical Sciences

160

168

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Summary Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases and heparanases. HS has important emerging roles in oncogenesis and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network.

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“…Fujita et al 68 report that downregulation of telomere repeat binding factor 2 (TRF2) is involved in the onset of cellular senescence. Furthermore, Biroccio et al 69 show that HS3ST4, which is positively regulated by TRF2, inhibits the recruitment of natural killer (NK) cells. Based on these previous reports and our present results, we propose that cell surface HS sulfation could trigger cellular senescence by modulating receptor signaling and could modify innate immune surveillance by affecting sulfated HS recognition by NK cells.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfation is essential for the prevention of cellular senescence

et al. 2015

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Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

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TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Cited by 105 publications

References 61 publications

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Heparan sulfate signaling in cancer

Heparan sulfation is essential for the prevention of cellular senescence

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