美国丹娜-法伯癌症研究所Ramesh A. Shivdasani课题组发现，隐窝密度和招募的增强子是肠道肿瘤发生的基础。相关论文于2025年1月8日在线发表在《自然》杂志上。

研究人员表示，驱动结直肠癌的致癌突变可以在健康肠道中存在很长时间，而不会产生明显的后果。腺瘤性息肉病基因（Apc）的突变是常规腺瘤中最常见的启动事件，它激活了Wnt信号通路，从而赋予突变肠道干细胞（ISC）生长优势。Apc突变可能发生在通过常规自我更新产生的ISC中，或通过其后代的去分化形成的ISC中。

尽管这些不同来源的ISC在本质上是相似的，但目前尚不清楚它们是否在未受损的肠道中同样有效地产生肿瘤。同时也不清楚在Wnt过度激活或随后的肿瘤特征中，顺式调控元件是否会发生实质性的调节。

研究人员通过两种小鼠模型发现，腺瘤并不是Apc缺失在任何ISC来源中都必然的结果，而是需要突变肠道隐窝的邻近。减少隐窝密度会阻止腺瘤形成，而突变的结肠隐窝聚集则增强了腺瘤的形成。此外，腺瘤中的ISC在数千个增强子上开放了染色质，这些增强子在与腺瘤无关的Apc缺失ISC中是无法可及的。

这些顺式元件解释了腺瘤选择性基因活动，并在其他致癌突变积累时持续存在，且几乎没有进一步扩展谱系。因此，邻近的突变隐窝之间的协同作用和特定增强子的新可及性，是肠道肿瘤发生早期的关键步骤。

附：英文原文

Title: Crypt density and recruited enhancers underlie intestinal tumour initiation

Author: Gaynor, Liam, Singh, Harshabad, Tie, Guodong, Badarinath, Krithika, Madha, Shariq, Mancini, Andrew, Bhattacharya, Swarnabh, Hoshino, Mikio, de Sauvage, Frederic J., Murata, Kazutaka, Jadhav, Unmesh, Shivdasani, Ramesh A.

Issue&Volume: 2025-01-08

Abstract: Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas3, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.

DOI: 10.1038/s41586-024-08573-9

Source: https://www.nature.com/articles/s41586-024-08573-9