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Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.
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.
Affiliation
  • Yang L; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Tu L; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China.
  • Bisht S; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • Mao Y; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Petkovich D; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Thursby SJ; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Liang J; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Patel N; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Yen RC; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Largent T; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Zahnow C; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Brock M; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Gabrielson K; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
  • Salimian KJ; Department of Comparative Medicine, Johns Hopkins Medical Institutions, 863 Broadway Research Building, 733 N. Broadway, Baltimore, MD, 21205-2196, USA.
  • Baylin SB; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
  • Easwaran H; CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD, 21287, USA.
Nat Commun ; 15(1): 1384, 2024 Feb 15.
Article in En | MEDLINE | ID: mdl-38360902
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colonic Neoplasms / Proto-Oncogene Proteins B-raf Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colonic Neoplasms / Proto-Oncogene Proteins B-raf Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Estados Unidos