Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system

Sandor Spisak, David Chen, Pornlada Likasitwatanakul, Paul Doan, Zhixin Li, Pratyusha Bala, Laura Vizkeleti, Viktoria Tisza, Pushpamali Silva, Marios Giannakis, Brian Wolpin, Jun Qi and Nilay S. Sethi ()
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Sandor Spisak: Dana-Farber Cancer Institute
David Chen: Dana-Farber Cancer Institute
Pornlada Likasitwatanakul: Dana-Farber Cancer Institute
Paul Doan: Dana-Farber Cancer Institute
Zhixin Li: Dana-Farber Cancer Institute
Pratyusha Bala: Dana-Farber Cancer Institute
Laura Vizkeleti: Faculty of Medicine, Semmelweis University
Viktoria Tisza: Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences
Pushpamali Silva: Dana-Farber Cancer Institute
Marios Giannakis: Dana-Farber Cancer Institute
Brian Wolpin: Dana-Farber Cancer Institute
Jun Qi: Dana-Farber Cancer Institute
Nilay S. Sethi: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46285-w

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