Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer.
Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer.
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DOI：
10.1016/j.cell.2017.06.031
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发表时间：
2017-07-13
期刊：
影响因子：
64.5
通讯作者：
Minn AJ
中科院分区：
文献类型：
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作者：
Nabet BY;Qiu Y;Shabason JE;Wu TJ;Yoon T;Kim BC;Benci JL;DeMichele AM;Tchou J;Marcotrigiano J;Minn AJ
基质成纤维细胞和癌细胞之间的相互作用产生癌症进展、治疗抵抗和炎症反应的信号。尽管作为模式识别受体 (PRR) 的损伤相关分子模式 (DAMP) 的内源性 RNA 可能代表了一种这样的信号，但这些 RNA 在非病理条件下必须保持未被识别。我们发现，乳腺癌细胞触发基质 NOTCH-MYC 会导致 POL3 驱动的 RN7SL1 增加，RN7SL1 是一种通常被 RNA 结合蛋白 SRP9/14 屏蔽的内源性 RNA。 RN7SL1 的增加改变了其与 SRP9/14 的化学计量，并在基质外泌体中产生未屏蔽的 RN7SL1。外泌体转移至免疫细胞后，未屏蔽的 RN7SL1 会引发炎症反应。转移到乳腺癌细胞后，未屏蔽的 RN7SL1 会激活 PRR RIG-I，以增强肿瘤生长、转移和治疗耐药性。来自患者肿瘤和血液的证据证实，这些结果表明，RNA 去屏蔽的调节将基质激活与 RNA DAMP 的部署相结合，从而促进癌症的侵袭性特征。基质细胞脱落的外泌体含有一种RNA，这种RNA以无蛋白的形式驱动受体乳腺癌细胞中的抗病毒信号传导，最终导致肿瘤生长和治疗耐药。
Interactions between stromal fibroblasts and cancer cells generate signals for cancer progression, therapy resistance, and inflammatory responses. Although endogenous RNAs acting as damage-associated molecular patterns (DAMPs) for pattern recognition receptors (PRRs) may represent one such signal, these RNAs must remain unrecognized under non-pathological conditions. We show that triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous RNA normally shielded by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 in stromal exosomes. After exosome transfer to immune cells, unshielded RN7SL1 drives an inflammatory response. Upon transfer to breast cancer cells, unshielded RN7SL1 activates the PRR RIG-I to enhance tumor growth, metastasis, and therapy resistance. Corroborated by evidence from patient tumors and blood, these results demonstrate that regulation of RNA unshielding couples stromal activation with deployment of RNA DAMPs that promote aggressive features of cancer. Stromal cells shed exosomes containing an RNA that, in its protein-free form, drives anti-viral signaling in recipient breast cancer cells that ultimately results in tumor growth as well as therapy resistance.
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影响因子：
64.5
作者：
Boelens MC;Wu TJ;Nabet BY;Xu B;Qiu Y;Yoon T;Azzam DJ;Twyman-Saint Victor C;Wiemann BZ;Ishwaran H;Ter Brugge PJ;Jonkers J;Slingerland J;Minn AJ
通讯作者：
Minn AJ
DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
影响因子：
64.8
作者：
Saito, Takeshi;Owen, David M.;Gale, Michael, Jr.
通讯作者：
Gale, Michael, Jr.
影响因子：
50.3
作者：
Becker A;Thakur BK;Weiss JM;Kim HS;Peinado H;Lyden D
通讯作者：
Lyden D
影响因子：
30.5
作者：
通讯作者：
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