生物
癌症研究
祖细胞
人口
结直肠癌
基因沉默
癌症干细胞
转移
DNA甲基化
癌症
干细胞
细胞生物学
遗传学
医学
基因
基因表达
环境卫生
作者
Samuel A. Miller,Robert A. Policastro,Shruthi Sriramkumar,Tim Lai,Thomas D. Huntington,Christopher A. Ladaika,Daeho Kim,Chunhai Hao,Gabriel E. Zentner,Heather M. O’Hagan
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-05-25
卷期号:81 (14): 3791-3805
被引量:41
标识
DOI:10.1158/0008-5472.can-20-3562
摘要
Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer histologic subtypes, their role in colorectal cancer progression has been underexplored. Here, our analysis of The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data demonstrates that EEC progenitor cells are enriched in BRAF-mutant colorectal cancer patient tumors, cell lines, and patient-derived organoids. In BRAF-mutant colorectal cancer, EEC progenitors were blocked from differentiating further by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of intermediate EECs. Mechanistically, secretory cells and the factors they secrete, such as trefoil factor 3, promoted colony formation and activation of cell survival pathways in the entire cell population. Lysine-specific demethylase 1 (LSD1) was identified as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss blocks formation of EEC progenitors and reduces tumor growth and metastasis. These findings reveal an important role for EEC progenitors in supporting colorectal cancer. SIGNIFICANCE: This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth.
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