Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer

Publication date: 13 July 2017
Source:Cell, Volume 170, Issue 2
Author(s): Barzin Y. Nabet, Yu Qiu, Jacob E. Shabason, Tony J. Wu, Taewon Yoon, Brian C. Kim, Joseph L. Benci, Angela M. DeMichele, Julia Tchou, Joseph Marcotrigiano, Andy J. Minn
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

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Teaser

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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