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- Title
Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.
- Authors
Yang, Lijing; Tu, Lei; Bisht, Shilpa; Mao, Yiqing; Petkovich, Daniel; Thursby, Sara-Jayne; Liang, Jinxiao; Patel, Nibedita; Yen, Ray-Whay Chiu; Largent, Tina; Zahnow, Cynthia; Brock, Malcolm; Gabrielson, Kathy; Salimian, Kevan J.; Baylin, Stephen B.; Easwaran, Hariharan
- 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. Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Subjects
COLON cancer; COLON tumors; DNA methylation; TRANSCRIPTION factors; STEM cells
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45605-4