️ Episode 204: StealTHY CRISPR: Revealing Hidden Metastasis Regulators

In this episode of PaperCast Base by Base, we explore how the StealTHY CRISPR platform sidesteps Cas9 immunogenicity to uncover metastasis drivers in immunocompetent and humanized cancer models.

Study Highlights:
Researchers show that standard CRISPR-Cas9 tools and xenogeneic reporters provoke strong T cell responses in syngeneic and humanized mice, reshaping clonal architecture and suppressing metastasis.
To overcome this, they develop StealTHY, a “hit-and-run” knockout strategy that pairs species-autologous Thy1 reporters with transient delivery of Cas9 protein, eliminating persistent immunogenic transgenes while preserving sgRNA library complexity.
Across multiple murine breast, lung, and colon carcinoma models, StealTHY restores polyclonal tumor growth, enables unbiased in vivo CRISPR screens, and reveals context-specific dependencies in receptor tyrosine kinase and TGF-β signaling pathways.
Applying StealTHY to human breast cancer in humanized mice, the authors identify clinically relevant metastasis regulators and derive gene signatures whose expression stratifies prognosis in large breast, lung, and colon cancer cohorts.
A central discovery is that the developmental AMH–AMHR2 axis acts as an immune-evasive driver of carcinoma metastasis, and its genetic or pharmacologic disruption enhances anti-tumor immunity, reduces circulating tumor cell clusters, and limits metastatic spread.

Conclusion:
Together, these findings position StealTHY as a broadly applicable, immune-compatible CRISPR screening platform that can expose metastasis vulnerabilities and nominate immunomodulatory pathways such as AMH–AMHR2 for future therapeutic targeting.

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Saini M, Castro-Giner F, Hotz A, et al. StealTHY: An immunogen-free CRISPR platform to expose concealed metastasis regulators in immunocompetent models. Cell. 2025;188:1–19. https://doi.org/10.1016/j.cell.2025.10.007

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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