Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Issued Date
2024-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85187639524
Journal Title
Nature Communications
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.15 No.1 (2024)
Suggested Citation
Spisak S., Chen D., Likasitwatanakul P., Doan P., Li Z., Bala P., Vizkeleti L., Tisza V., De Silva P., Giannakis M., Wolpin B., Qi J., Sethi N.S. Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system. Nature Communications Vol.15 No.1 (2024). doi:10.1038/s41467-024-46285-w Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/97699
Title
Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Corresponding Author(s)
Other Contributor(s)
Abstract
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.