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

Barzin Y Nabet1, Yu Qiu1, Jacob E Shabason1

  • 1Department 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.

Cell
|July 15, 2017
PubMed

Insights

Breast cancer cells trigger stromal NOTCH-MYC, increasing RNA RN7SL1. Unshielded RN7SL1 in exosomes promotes inflammation, tumor growth, metastasis, and therapy resistance by activating pattern recognition receptors (PRRs).

Area of Science:

  • Molecular biology
  • Cancer research
  • Immunology

Background:

  • Stromal fibroblasts and cancer cells interact, influencing cancer progression and therapy resistance.
  • Endogenous RNAs can act as damage-associated molecular patterns (DAMPs) to activate pattern recognition receptors (PRRs), but are normally shielded.
  • Unshielded RNAs released by stromal cells can promote inflammation and cancer aggressiveness.

Purpose of the Study:

  • To investigate the role of stromal RNA regulation in cancer progression and therapy resistance.
  • To identify specific RNA molecules and pathways involved in stromal-cancer cell communication.
  • To understand how stromal activation leads to the release of inflammatory and tumor-promoting signals.

Main Methods:

  • Investigated NOTCH-MYC signaling in stromal fibroblasts triggered by breast cancer cells.
  • Analyzed the role of POL3 in regulating the expression of RNA RN7SL1.
  • Examined the interaction between RN7SL1 and RNA binding proteins SRP9/14.
  • Studied the transfer of unshielded RN7SL1 via exosomes to immune and cancer cells.
  • Assessed the activation of pattern recognition receptors (PRRs) like RIG-I.
  • Corroborated findings using patient tumor and blood samples.

Main Results:

  • Breast cancer cells trigger stromal NOTCH-MYC, leading to increased RN7SL1 expression.
  • Increased RN7SL1 alters its binding with SRP9/14, resulting in unshielded RN7SL1.
  • Unshielded RN7SL1 is released in stromal exosomes and transferred to other cells.
  • In immune cells, unshielded RN7SL1 drives an inflammatory response.
  • In breast cancer cells, unshielded RN7SL1 activates RIG-I, enhancing tumor growth, metastasis, and therapy resistance.
  • Evidence from patient samples supports the role of RNA unshielding in aggressive cancer features.

Conclusions:

  • Regulation of RNA unshielding is a key mechanism coupling stromal activation with the release of RNA DAMPs.
  • Unshielded RN7SL1 promotes aggressive cancer phenotypes, including growth, metastasis, and therapy resistance.
  • Targeting RNA unshielding pathways may offer novel therapeutic strategies for breast cancer.
Keywords:
RIG-IRNA binding proteinsbreast cancerexosomesfibroblastspattern recognition receptorsradiation therapyshieldingstromal activationtumor microenvironment

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