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Proc Natl Acad Sci U S A 2021 Nov 23;11847:. doi: 10.1073/pnas.2115116118.
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CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping.

Naert T , Tulkens D , Van Nieuwenhuysen T , Przybyl J , Demuynck S , van de Rijn M , Al-Jazrawe M , Alman BA , Coucke PJ , De Leeneer K , Vanhove C , Savvides SN , Creytens D , Vleminckx K .

Cancer precision medicine implies identification of tumor-specific vulnerabilities associated with defined oncogenic pathways. Desmoid tumors are soft-tissue neoplasms strictly driven by Wnt signaling network hyperactivation. Despite this clearly defined genetic etiology and the strict and unique implication of the Wnt/β-catenin pathway, no specific molecular targets for these tumors have been identified. To address this caveat, we developed fast, efficient, and penetrant genetic Xenopus tropicalis desmoid tumor models to identify and characterize drug targets. We used multiplexed CRISPR/Cas9 genome editing in these models to simultaneously target a tumor suppressor gene (apc) and candidate dependency genes. Our methodology CRISPR/Cas9 selection-mediated identification of dependencies (CRISPR-SID) uses calculated deviations between experimentally observed gene editing outcomes and deep-learning-predicted double-strand break repair patterns to identify genes under negative selection during tumorigenesis. This revealed EZH2 and SUZ12, both encoding polycomb repressive complex 2 components, and the transcription factor CREB3L1 as genetic dependencies for desmoid tumors. In vivo EZH2 inhibition by Tazemetostat induced partial regression of established autochthonous tumors. In vitro models of patient desmoid tumor cells revealed a direct effect of Tazemetostat on Wnt pathway activity. CRISPR-SID represents a potent approach for in vivo mapping of tumor vulnerabilities and drug target identification.

PubMed ID: 34789568
PMC ID: PMC8617425
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: adam12 apc axin2 col1a1 creb3l1 ctnnb1 ezh2 fap hmmr lox mdk myc nuak1 pclaf pycr1 suz12 tgfb2
Antibodies: Actb Ab9 Creb3l1 Ab1 Ezh2 Ab4 H3f3a Ab24 H3f3a Ab33 H3f3a Ab44 Myc Ab7

Disease Ontology terms: hereditary desmoid disease [+]

Article Images: [+] show captions
References [+] :
Alman, Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). 1997, Pubmed