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.
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China.
Nat Commun. 2024 Feb 15;15(1):1384. doi: 10.1038/s41467-024-45605-4.
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 BRAF 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 BRAF-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.
同一组织类型但在解剖位置上不同的癌症在肿瘤发生方面表现出不同的分子依赖性。近端结肠癌和远端结肠癌就是这种特征的典型代表，BRAF 主要发生在近端结肠癌中，同时伴有 DNA 甲基化表型增加。在这里，我们使用小鼠结肠类器官表明，近端和远端结肠干细胞具有不同的转录程序，调节干细胞特性和分化。我们发现，同源盒转录因子 CDX2 在近端结肠癌中被 DNA 甲基化沉默，是差异转录程序的关键介质。Cdx2 介导的近端结肠特异性转录程序同时具有肿瘤抑制作用，Cdx2 的缺失足以使 BRAF 驱动的转化成为可能。CDX2 下调的人近端结肠癌表现出与小鼠近端类器官中 Cdx2 缺失相似的转录程序。发育转录因子，如 CDX2，对于维持组织位置特异性转录程序至关重要，这些程序为肿瘤发展创造了组织类型起源特异性的依赖性。
