CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer
Authors
Mou, HaiweiEskiocak, Onur
Özler, Kadir A
Gorman, Megan
Yue, Junjiayu
Jin, Ying
Wang, Zhikai
Gao, Ya
Janowitz, Tobias
Meyer, Hannah V
Yu, Tianxiong
Wilkinson, John E
Kucukural, Alper
Ozata, Deniz M
Beyaz, Semir
UMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyDocument Type
Journal ArticlePublication Date
2023-02-08Keywords
CRISPR/Cas9exon skipping
hepatoblastoma
hepatocellular carcinoma
liver cancer
β-catenin
UMCCTS funding
Metadata
Show full item recordAbstract
CRISPR/Cas9-driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of Ctnnb1 induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon-skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Source
Mou H, Eskiocak O, Özler KA, Gorman M, Yue J, Jin Y, Wang Z, Gao Y, Janowitz T, Meyer HV, Yu T, Wilkinson JE, Kucukural A, Ozata DM, Beyaz S. CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer. J Pathol. 2023 Apr;259(4):415-427. doi: 10.1002/path.6054. Epub 2023 Feb 8. PMID: 36641763.DOI
10.1002/path.6054Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51777PubMed ID
36641763Rights
© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1002/path.6054
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Except where otherwise noted, this item's license is described as © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.