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Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer

Amir Hosseini1, Håvard T Lindholm2, Raymond Chen3

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.

Cell Reports
|January 23, 2024
PubMed

Insights

Viral mimicry, triggered by endogenous double-stranded RNA (dsRNA), can be exploited to target cancer. Researchers found the RNA decay protein XRN1 is essential for survival in some cancer cells, suggesting it as a therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Viral mimicry involves immune responses to endogenous stimuli like double-stranded RNA (dsRNA).
  • Activating viral mimicry shows potential for cancer cell death and enhanced anti-tumor immunity.

Purpose of the Study:

  • To systematically identify mechanisms of viral mimicry adaptation linked to cancer cell dependencies.
  • To explore the role of the RNA decay protein XRN1 in cancer cell survival and viral mimicry.

Main Methods:

  • Systematic identification of cancer cell dependencies related to viral mimicry.
  • Analysis of XRN1 dependency, mitochondrial antiviral signaling (MAVS), and protein kinase R (PKR) activation.
  • Quantification of cytosolic dsRNA, Alu elements, and interferon-stimulated gene expression.
  • Investigating the effects of dsRNA-inducing drugs (5-aza-2'-deoxycytidine, palbociclib) on XRN1 dependency.

Main Results:

  • XRN1 was identified as an essential gene for the survival of a subset of cancer cell lines.
  • XRN1 dependency is linked to MAVS and PKR activation, increased cytosolic dsRNA, and elevated interferon-stimulated gene expression.
  • Cancer cells exhibiting these characteristics die due to induced viral mimicry.
  • dsRNA-inducing drugs created a synthetic dependency on XRN1 in resistant cancer cells.

Conclusions:

  • XRN1 is crucial for cancer cell survival under conditions of induced viral mimicry.
  • The interplay between XRN1, dsRNA, and innate immune signaling pathways is key to this dependency.
  • Targeting XRN1, potentially in combination with dsRNA-inducing agents, represents a promising therapeutic strategy for cancer treatment.
Keywords:
CP: CancerCP: ImmunologyXRN1endogenous retroelementsviral mimicry

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