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 and Hariharan Easwaran ()
Additional contact information
Lijing Yang: The Johns Hopkins University School of Medicine
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

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45605-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45605-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45605-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().