StealTHY: An immunogen-free CRISPR platform to expose concealed metastasis regulators in immunocompetent models
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Date
2025-12-24
Publication Type
Journal Article
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yes
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Abstract
CRISPR screens have become standard gene discovery platforms in various contexts, including cancer. Yet commonly available CRISPR-Cas9 tools are increasingly recognized as unfit for in vivo investigations in immunocompetent contexts, due to broad immunogenicity of bacterial nucleases and reporters. Here, we show how conventional CRISPR screens in tumor grafts are systematically jeopardized by immunoediting in syngeneic and humanized immunocompetent hosts, resulting in iatrogenic clonal dropouts and ultimately compromising target identification. To resolve this, we present StealTHY, an immunogen-free CRISPR platform compatible with virtually all immunocompetent designs, enabling preservation of clonal architecture and exposing previously concealed cancer vulnerabilities. Among these, we identify the AMH-AMHR2 axis as a formerly unappreciated metastasis target. Thus, with StealTHY, we provide a new resource to expand the applicability of CRISPR screens to immunocompetent models, including humanized tumor grafts, revealing metastasis regulators of therapeutic relevance.
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published
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Journal / series
Volume
188 (26)
Pages / Article No.
7591 - 7.609e+35
Publisher
Cell Press
Event
Edition / version
Methods
Software
Geographic location
Date collected
Date created
Subject
CRISPR; Cas9; Cancer; Metastasis; Preclinical models of cancer; Humanized mice; Patient-derived xenografts; Cancer immunogenicity; Anti-tumor immunity
Organisational unit
09736 - Aceto, Nicola / Aceto, Nicola
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
Notes
Funding
101001652 - Tumor-lock: forbid the generation of circulating tumor cells (EC)
212183 - CRISPR screen for immunotherapy sensitizers in humanized circulating tumor cell xenografts (SNF)
231353 - 10002279 - 3D spatial identification of intravasation-prone tumor regions (SNF)
212183 - CRISPR screen for immunotherapy sensitizers in humanized circulating tumor cell xenografts (SNF)
231353 - 10002279 - 3D spatial identification of intravasation-prone tumor regions (SNF)