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

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 Gabrielson, Kevan J. Salimian, Stephen B. Baylin, Hariharan Easwaran

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number1384
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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