缺乏Wnt和缺氧的环境协调了人类胰腺管道腺癌的状重编程
Hiroki Tamagawa1,2,3, Masayuki Fujii4,5, Kazuhiro Togasaki1,2,3
1Department of Organoid Medicine, Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, Japan.
Nature cell biology
|September 4, 2024
概括
人类胰腺癌细胞可以转换为状细胞身份,由表观遗传变化和TP63.3驱动. 这种血统转换在具有挑战性的瘤微环境中提高了生存率.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 人类胰腺癌表现出分子多样性,包括管状和状细胞状表型.
- 在胰腺癌中驱动状转分化的机制尚不清楚.
研究的目的:
- 研究人类胰腺癌中状转基因差异化的分子驱动因素和表观遗传机制.
- 描述血统转换在胰腺癌演变和适应中的作用.
主要方法:
- 65个来自患者的胰腺癌器官系的概况,包括状腺癌.
- 对正常的胰腺管器官进行基因工程,以研究状细胞重编程.
- 对表观遗传修饰 (H3K27me3,KDM6A) 和关键转录因子 (TP63,GATA6) 的分析.
主要成果:
- 由于H3K27me3的介导,导管身份的丧失和TP63的激活驱动了状细胞的结合.
- GATA6损失,Wnt缺乏和KDM6A无活化促进状重编程.
- 状转基因差异化在Wnt缺乏和缺氧条件下提供了生存优势.
- 抑制EZH2逆转了表观遗传变化,并抑制了状腺癌的生长.
结论:
- 一个敌对的微环境决定了人类胰腺癌的分子和组织进化.
- 血统转换是人类癌症的一个重要机制,受表观遗传调节和微环境线索的影响.
- 针对像EZH2这样的表观遗传调节者,可能为状腺癌提供治疗策略.
相关概念视频
Canonical Wnt Signaling Pathway
8.7K
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
8.7K
Non-Canonical Wnt Signaling Pathways
7.3K
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
7.3K
Role Of Notch Signalling In Intestinal Stem Cell Renewal
2.1K
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.1K


