IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46285-w.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46285-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46285-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    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 Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sanju Sinha & Karina Barbosa & Kuoyuan Cheng & Mark D. M. Leiserson & Prashant Jain & Anagha Deshpande & David M. Wilson & Bríd M. Ryan & Ji Luo & Ze’ev A. Ronai & Joo Sang Lee & Aniruddha J. Deshpand, 2021. "A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    3. Hyeong-Min Lee & William C. Wright & Min Pan & Jonathan Low & Duane Currier & Jie Fang & Shivendra Singh & Stephanie Nance & Ian Delahunty & Yuna Kim & Richard H. Chapple & Yinwen Zhang & Xueying Liu , 2023. "A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Jurica Levatić & Marina Salvadores & Francisco Fuster-Tormo & Fran Supek, 2022. "Mutational signatures are markers of drug sensitivity of cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Han Jin & Cheng Zhang & Martin Zwahlen & Kalle Feilitzen & Max Karlsson & Mengnan Shi & Meng Yuan & Xiya Song & Xiangyu Li & Hong Yang & Hasan Turkez & Linn Fagerberg & Mathias Uhlén & Adil Mardinoglu, 2023. "Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Seungyeul Yoo & Abhilasha Sinha & Dawei Yang & Nasser K. Altorki & Radhika Tandon & Wenhui Wang & Deebly Chavez & Eunjee Lee & Ayushi S. Patel & Takashi Sato & Ranran Kong & Bisen Ding & Eric E. Schad, 2022. "Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Alon Stern & Mariam Fokra & Boris Sarvin & Ahmad Abed Alrahem & Won Dong Lee & Elina Aizenshtein & Nikita Sarvin & Tomer Shlomi, 2023. "Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    9. Sayantani Ghosh Dastidar & Bony Kumar & Bo Lauckner & Damien Parrello & Danielle Perley & Maria Vlasenok & Antariksh Tyagi & Nii Koney-Kwaku Koney & Ata Abbas & Sergei Nechaev, 2023. "Transcriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Sumana Srivatsa & Hesam Montazeri & Gaia Bianco & Mairene Coto-Llerena & Mattia Marinucci & Charlotte K. Y. Ng & Salvatore Piscuoglio & Niko Beerenwinkel, 2022. "Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Cemal Erdem & Sean M. Gross & Laura M. Heiser & Marc R. Birtwistle, 2023. "MOBILE pipeline enables identification of context-specific networks and regulatory mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Adam E. Hall & Sebastian Öther-Gee Pohl & Patrizia Cammareri & Stuart Aitken & Nicholas T. Younger & Michela Raponi & Caroline V. Billard & Alfonso Bolado Carrancio & Aslihan Bastem & Paz Freile & Fio, 2022. "RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    13. Guidantonio Malagoli Tagliazucchi & Anna J. Wiecek & Eloise Withnell & Maria Secrier, 2023. "Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    14. Souleymane Abdoul-Azize & Rihab Hami & Gaetan Riou & Céline Derambure & Camille Charbonnier & Jean-Pierre Vannier & Monica L. Guzman & Pascale Schneider & Olivier Boyer, 2024. "Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    15. Philip East & Gavin P. Kelly & Dhruva Biswas & Michela Marani & David C. Hancock & Todd Creasy & Kris Sachsenmeier & Charles Swanton & Julian Downward & Sophie de Carné Trécesson, 2022. "RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    17. Carolin Ector & Christoph Schmal & Jeff Didier & Sébastien De Landtsheer & Anna-Marie Finger & Francesca Müller-Marquardt & Johannes H. Schulte & Thomas Sauter & Ulrich Keilholz & Hanspeter Herzel & A, 2024. "Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Zheqi Li & Olivia McGinn & Yang Wu & Amir Bahreini & Nolan M. Priedigkeit & Kai Ding & Sayali Onkar & Caleb Lampenfeld & Carol A. Sartorius & Lori Miller & Margaret Rosenzweig & Ofir Cohen & Nikhil Wa, 2022. "ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    19. Bingzhen Chen & Wenjuan Zhai & Lingchen Kong, 2022. "Variable selection and collinearity processing for multivariate data via row-elastic-net regularization," AStA Advances in Statistical Analysis, Springer;German Statistical Society, vol. 106(1), pages 79-96, March.
    20. Hao Wang & R. Alejandro Sica & Gurbakhash Kaur & Phillip M. Galbo & Zhixin Jing & Christopher D. Nishimura & Xiaoxin Ren & Ankit Tanwar & Bijan Etemad-Gilbertson & Britta Will & Deyou Zheng & David Fo, 2024. "TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46285-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.