Lineage Reversion Drives WNT Independence in Intestinal Cancer.
Lineage Reversion Drives WNT Independence in Intestinal Cancer.
复制标题
谱系逆转驱动肠癌中WNT的独立性。
DOI：
10.1158/2159-8290.cd-19-1536
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发表时间：
2020-10
期刊：
影响因子：
28.2
通讯作者：
Dow LE
中科院分区：
文献类型：
--
作者：
Han T;Goswami S;Hu Y;Tang F;Zafra MP;Murphy C;Cao Z;Poirier JT;Khurana E;Elemento O;Hechtman JF;Ganesh K;Yaeger R;Dow LE
WNT通路是肠道内稳态的基本调节器，并且WNT信号传导的过度活化是结直肠癌（CRC）中的主要致癌驱动因素。迄今为止，没有描述的机制，绕过WNT依赖性在肠道肿瘤。在这里，我们表明，虽然WNT抑制阻断了大多数类器官和体内CRC模型中的肿瘤生长，但CRC相关遗传改变的积累使耐药性和WNT非依赖性生长成为可能。在含有KRAS或BRAF突变以及p53和SMAD 4破坏的肠上皮细胞中，短暂的TGFβ暴露会驱动雅普/TAZ依赖性转录重编程和谱系逆转。胚胎肠道特性的获得伴随着成年肠道谱系的永久性丧失和长期WNT非依赖性生长。这项工作确定了驱动WNT抑制剂耐药性的遗传和微环境因素，定义了WNT非依赖性CRC生长的新机制，并揭示了相关遗传改变和细胞外信号的整合如何克服谱系依赖性致癌程序。
The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.