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Tissue-location-specific transcription programs drive tumor dependencies in colon cancer

Author

Listed:
  • Lijing Yang

    (The Johns Hopkins University School of Medicine
    Zhongnan Hospital of Wuhan University)

  • Lei Tu

    (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology)

  • Shilpa Bisht

    (The Johns Hopkins University School of Medicine)

  • Yiqing Mao

    (The Johns Hopkins University School of Medicine)

  • Daniel Petkovich

    (The Johns Hopkins University School of Medicine)

  • Sara-Jayne Thursby

    (The Johns Hopkins University School of Medicine)

  • Jinxiao Liang

    (The Johns Hopkins University School of Medicine)

  • Nibedita Patel

    (The Johns Hopkins University School of Medicine)

  • Ray-Whay Chiu Yen

    (The Johns Hopkins University School of Medicine)

  • Tina Largent

    (The Johns Hopkins University School of Medicine)

  • Cynthia Zahnow

    (The Johns Hopkins University School of Medicine)

  • Malcolm Brock

    (The Johns Hopkins University School of Medicine)

  • Kathy Gabrielson

    (Johns Hopkins Medical Institutions)

  • Kevan J. Salimian

    (The Johns Hopkins University School of Medicine)

  • Stephen B. Baylin

    (The Johns Hopkins University School of Medicine)

  • Hariharan Easwaran

    (The Johns Hopkins University School of Medicine)

Abstract

Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.

Suggested Citation

  • Lijing Yang & Lei Tu & Shilpa Bisht & Yiqing Mao & Daniel Petkovich & Sara-Jayne Thursby & Jinxiao Liang & Nibedita Patel & Ray-Whay Chiu Yen & Tina Largent & Cynthia Zahnow & Malcolm Brock & Kathy Ga, 2024. "Tissue-location-specific transcription programs drive tumor dependencies in colon cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45605-4
    DOI: 10.1038/s41467-024-45605-4
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    References listed on IDEAS

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    1. Wenjing Bai & Jinxin Xu & Wenbin Gu & Danyang Wang & Ying Cui & Weidong Rong & Xiaoan Du & Xiaoxia Li & Cuicui Xia & Qingqing Gan & Guantao He & Huahui Guo & Jinfeng Deng & Yuqiong Wu & Ray-Whay Chiu , 2025. "Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-22, December.

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