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The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response

William Dunker1, Shivam A Zaver1,2, Jose Mario Bello Pineda2,3,4

  • 1Department of Microbiology and.

JCI Insight
|May 11, 2023
PubMed

Insights

The proto-oncogene SRC inhibits the antitumor immune response by blocking Cyclic GMP-AMP synthase (cGAS) signaling in bladder cancer. Targeting SRC may restore cGAS function and enhance cancer immunity.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor that triggers antitumor immune responses.
  • cGAS activity is often suppressed in various cancers, limiting therapeutic strategies.
  • SRC, a proto-oncogene tyrosine kinase, is overexpressed in many cancers.

Purpose of the Study:

  • To investigate the role of SRC in regulating cGAS-mediated antitumor immunity in bladder cancer.
  • To elucidate the molecular mechanisms by which SRC affects cGAS signaling.

Main Methods:

  • Correlation analysis of SRC expression with immune markers in bladder cancer.
  • In vitro studies using human cell lines with SRC inhibition, depletion, and overexpression.
  • Biochemical assays to determine SRC's direct effect on cGAS activity and phosphorylation.

Main Results:

  • SRC expression inversely correlates with innate immune gene expression and immune cell infiltration in bladder cancer.
  • SRC directly interacts with cGAS and inhibits its enzymatic activity and DNA binding in a kinase-dependent manner.
  • SRC phosphorylates cGAS at Y248, partially contributing to cGAS inhibition.

Conclusions:

  • The proto-oncogene SRC suppresses cGAS-driven antitumor immunity in bladder cancer.
  • SRC represents a potential therapeutic target to reactivate cGAS signaling and enhance anti-tumor immune responses.
Keywords:
Cancer immunotherapyImmunologyInnate immunityOncology

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