Nabet Barzin Y, Qiu Yu, Shabason Jacob E, Wu Tony J, Yoon Taewon, Kim Brian C, Benci Joseph L, DeMichele Angela M, Tchou Julia, Marcotrigiano Joseph, Minn Andy J
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Cell. 2017 Jul 13;170(2):352-366.e13. doi: 10.1016/j.cell.2017.06.031.
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. VIDEO ABSTRACT.
基质成纤维细胞与癌细胞之间的相互作用会产生促进癌症进展、治疗抗性和炎症反应的信号。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可能代表这样一种信号，但这些RNA在非病理条件下必须保持未被识别状态。我们发现，乳腺癌细胞触发基质中的NOTCH-MYC会导致POL3驱动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的这种增加改变了其与SRP9/14的化学计量，并在基质外泌体中产生未被屏蔽的RN7SL1。外泌体转移到免疫细胞后，未被屏蔽的RN7SL1会引发炎症反应。转移到乳腺癌细胞后，未被屏蔽的RN7SL1会激活PRR RIG-I，以增强肿瘤生长、转移和治疗抗性。来自患者肿瘤和血液的证据证实了这些结果，表明RNA去屏蔽的调节将基质激活与促进癌症侵袭性特征的RNA DAMP的部署联系起来。视频摘要。
