[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-333161-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-333161-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","tissue-location-specific-transcription-programs-drive-tumor-dependencies-in-colon-cancer","Tissue-location-specific transcription programs drive tumor dependencies in colon cancer","","Tissue-type cancers can display different molecular dependencies depending on their anatomical location. Proximal and distal colon cancers show distinct driver patterns, including BRAFV600E enrichment in proximal disease alongside higher DNA methylation phenotypes. Using mouse colon organoids, the work identifies different transcriptional programs in proximal versus distal stem cells that regulate stemness and differentiation. The homeobox factor CDX2, silenced by DNA methylation in proximal cancers, is identified as a key mediator.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/tissue-location-specific-transcription-programs-drive-tumor-dependencies-in-colon-cancer/333161/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/tissue-location-specific-transcription-programs-drive-tumor-dependencies-in-colon-cancer/333161.png","ImageObject",300,407,{"name":42,"@type":43},"Patrick","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why do cancers of the same tissue type differ between proximal and distal colon?","Question",{"text":63,"@type":64},"They can rely on different molecular dependencies due to differences in transcriptional and epigenetic context along the colon axis.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What role does BRAFV600E play in proximal colon cancer?",{"text":68,"@type":64},"BRAFV600E is predominantly associated with proximal colon cancers and occurs together with increased DNA methylation phenotypes.",{"name":70,"@type":61,"acceptedAnswer":71},"How does CDX2 influence tumor development in this study?",{"text":72,"@type":64},"CDX2 is silenced by DNA methylation in proximal cancers; restoring or maintaining its regulated program is tumor-suppressive, while CDX2 loss creates a permissive state for BRAFV600E-driven transformation.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},333161,1790164110,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},7,"Healthcare",40,"healthcare",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":113,"slug":114},8,30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":112,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Article [https://doi.org/10.1038/s41467-024-45605-4](https://doi.org/10.1038/s41467-024-45605-4)  \nTissue-location-specific transcription programs drive tumor dependencies in colon cancer  \nReceived: 16 May 2023  \n\n| Accepted: 30 January 2024 |\n| --- |\n| |\n| Check for updates |\n\nLijing Yang1,2,6, Lei Tu3,6, Shilpa Bisht 1, Yiqing Mao1, Daniel Petkovich  Sara-Jayne Thursby1, Jinxiao Liang1, Nibedita Patel1, Ray-Whay Chiu Yen1, Tina Largent1, Cynthia Zahnow1, Malcolm Brock1, Kathy Gabrielson4, Kevan J. Salimian5, Stephen B. Baylin 1 & Hariharan Easwaran 1   \n1  \n,  \nCancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximaland 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.  \nCancers occurring in different anatomical sites within same tissue type and organ can exhibit stark differences in molecular, pathological, and clinical features. Colon cancers exemplify such features wherein thereis an increased likelihood of exhibiting the CpG-island methylator phenotype high (CIMP-high or CIMP-H), microsatellite instability high (MSI-high) and having BRAF mutations to dominate in the cancers occurring in the proximal colon1,2. Distal colon tends to have CIMPLow, microsatellite stable (MSS), APC-mutant cancers, with an increased likelihood ofKRAS mutations3,4. The mutually exclusive BRAFand KRAS mutations provide alternate means of activating the MEK-  \nERK signaling pathway and function as critical cancer driver mutations in colon cancers. Genome-wide association studies have shown further differences in genetic risk factors in proximal and distal colon cancer5. Developmentally, the proximal colon derives from the midgut and extends from the cecum to the proximal two-thirds ofthe transverse colon, while distal colon derives from the hindgut and extends from the distal third of the transverse colon to the sigmoid colon6. Anatomically, the proximal and distal colons have distinct blood supplies, with the superior and inferior mesenteric arteries supplying to proximal and distal colon respectively6. And microenvironmentally,  \n1CRB1, 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. 2Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China. 3Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 4Department of Comparative Medicine, Johns Hopkins Medical Institutions, 863 Broadway Research Building, 733 N. Broadway, Baltimore, MD 21205-2196, USA. 5Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 6These authors contributed equally: Lijing Yang, Lei Tu. e-mail: [heaswar1@jhmi.edu](heaswar1@jhmi.edu)  \nproximal and distal colon have differences in microbiome7,8 and expos","cbCaihFE6f0Bv7Dn","https://ap.wps.com/l/cbCaihFE6f0Bv7Dn","pdf",10975612,21,"English","# Introduction\n## Tissue-location differences in cancer dependencies\n## Molecular context and transcription factor programs\n# Proximal–distal colon transcriptional programs\n## CDX2 as a mediator\n## Effects of CDX2 loss on transformation\n# Implications for human disease","[{\"question\":\"Why do cancers of the same tissue type differ between proximal and distal colon?\",\"answer\":\"They can rely on different molecular dependencies due to differences in transcriptional and epigenetic context along the colon axis.\"},{\"question\":\"What role does BRAFV600E play in proximal colon cancer?\",\"answer\":\"BRAFV600E is predominantly associated with proximal colon cancers and occurs together with increased DNA methylation phenotypes.\"},{\"question\":\"How does CDX2 influence tumor development in this study?\",\"answer\":\"CDX2 is silenced by DNA methylation in proximal cancers; restoring or maintaining its regulated program is tumor-suppressive, while CDX2 loss creates a permissive state for BRAFV600E-driven transformation.\"}]","Tissue-location-specific transcription programs drive tumor dependencies in colon cancer | PDF",1790001204,53]