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

Author

Listed:
  • Sandor Spisak

    (Dana-Farber Cancer Institute
    Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences)

  • David Chen

    (Dana-Farber Cancer Institute
    University of Toronto)

  • Pornlada Likasitwatanakul

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University
    Faculty of Medicine Siriraj Hospital, Mahidol University)

  • Paul Doan

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University)

  • Zhixin Li

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University)

  • Pratyusha Bala

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University)

  • 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
    Harvard Medical School
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University
    Gastrointestinal Cancer Center, Dana-Farber Cancer Institute)

  • Brian Wolpin

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Gastrointestinal Cancer Center, Dana-Farber Cancer Institute)

  • Jun Qi

    (Dana-Farber Cancer Institute)

  • Nilay S. Sethi

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University
    Gastrointestinal Cancer Center, Dana-Farber Cancer Institute)

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.

Suggested Citation

  • Sandor Spisak & David Chen & Pornlada Likasitwatanakul & Paul Doan & Zhixin Li & Pratyusha Bala & Laura Vizkeleti & Viktoria Tisza & Pushpamali Silva & Marios Giannakis & Brian Wolpin & Jun Qi & Nilay, 2024. "Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46285-w
    DOI: 10.1038/s41467-024-46285-w
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    1. Lanbo Xiao & Abhijit Parolia & Yuanyuan Qiao & Pushpinder Bawa & Sanjana Eyunni & Rahul Mannan & Sandra E. Carson & Yu Chang & Xiaoju Wang & Yuping Zhang & Josh N. Vo & Steven Kregel & Stephanie A. Si, 2022. "Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer," Nature, Nature, vol. 601(7893), pages 434-439, January.
    2. Adam L. Haber & Moshe Biton & Noga Rogel & Rebecca H. Herbst & Karthik Shekhar & Christopher Smillie & Grace Burgin & Toni M. Delorey & Michael R. Howitt & Yarden Katz & Itay Tirosh & Semir Beyaz & Da, 2017. "A single-cell survey of the small intestinal epithelium," Nature, Nature, vol. 551(7680), pages 333-339, November.
    3. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J.Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Red, 2012. "Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 492(7428), pages 290-290, December.
    4. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J. Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    5. Mariko Shimokawa & Yuki Ohta & Shingo Nishikori & Mami Matano & Ai Takano & Masayuki Fujii & Shoichi Date & Shinya Sugimoto & Takanori Kanai & Toshiro Sato, 2017. "Visualization and targeting of LGR5+ human colon cancer stem cells," Nature, Nature, vol. 545(7653), pages 187-192, May.
    6. Jessica T. Cortez & Elena Montauti & Eric Shifrut & Jovylyn Gatchalian & Yusi Zhang & Oren Shaked & Yuanming Xu & Theodore L. Roth & Dimitre R. Simeonov & Yana Zhang & Siqi Chen & Zhongmei Li & Jonath, 2020. "CRISPR screen in regulatory T cells reveals modulators of Foxp3," Nature, Nature, vol. 582(7812), pages 416-420, June.
    7. Fiona M. Behan & Francesco Iorio & Gabriele Picco & Emanuel Gonçalves & Charlotte M. Beaver & Giorgia Migliardi & Rita Santos & Yanhua Rao & Francesco Sassi & Marika Pinnelli & Rizwan Ansari & Sarah H, 2019. "Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens," Nature, Nature, vol. 568(7753), pages 511-516, April.
    8. Johanna Grinat & Julian Heuberger & Ramon Oliveira Vidal & Neha Goveas & Frauke Kosel & Antoni Berenguer-Llergo & Andrea Kranz & Annika Wulf-Goldenberg & Diana Behrens & Bálint Melcher & Sascha Sauer , 2020. "The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    9. Zhexin Zhu & Xiaolong Chen & Ao Guo & Trishabelle Manzano & Patrick J. Walsh & Kendall M. Wills & Rebecca Halliburton & Sandi Radko-Juettner & Raymond D. Carter & Janet F. Partridge & Douglas R. Green, 2023. "Mitotic bookmarking by SWI/SNF subunits," Nature, Nature, vol. 618(7963), pages 180-187, June.
    10. Ron Firestein & Adam J. Bass & So Young Kim & Ian F. Dunn & Serena J. Silver & Isil Guney & Ellen Freed & Azra H. Ligon & Natalie Vena & Shuji Ogino & Milan G. Chheda & Pablo Tamayo & Stephen Finn & Y, 2008. "CDK8 is a colorectal cancer oncogene that regulates β-catenin activity," Nature, Nature, vol. 455(7212), pages 547-551, September.
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