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

Cell. 2017 Jul 13;170(2):352-366.e13. doi: 10.1016/j.cell.2017.06.031.

Abstract

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.

Keywords: RIG-I; RNA binding proteins; breast cancer; exosomes; fibroblasts; pattern recognition receptors; radiation therapy; shielding; stromal activation; tumor microenvironment.

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • DEAD Box Protein 58 / metabolism
  • Exosomes / metabolism
  • Exosomes / pathology*
  • Humans
  • Interferon Regulatory Factors / metabolism
  • MCF-7 Cells
  • Neoplasm Metastasis
  • RNA Polymerase III / genetics
  • RNA Polymerase III / metabolism
  • RNA, Untranslated / metabolism*
  • Receptors, Pattern Recognition / metabolism
  • Signal Recognition Particle / metabolism
  • Stromal Cells / metabolism
  • Stromal Cells / pathology*
  • Tumor Microenvironment*
  • Virus Diseases / metabolism

Substances

  • Interferon Regulatory Factors
  • RNA, Untranslated
  • Receptors, Pattern Recognition
  • SRP14 protein, human
  • SRP9 protein, human
  • Signal Recognition Particle
  • RNA Polymerase III
  • DDX58 protein, human
  • DEAD Box Protein 58