小柯机器人

科学家揭示肿瘤早期如何实现竞争优势
2021-06-03 11:37

美国哈佛医学院Owen J. Sansom、芬兰赫尔辛基大学Pekka Katajisto等研究人员合作发现,来自Apc突变细胞的NOTUM促进克隆竞争从而引发癌症。相关论文于2021年6月2日在线发表在《自然》杂志上。

研究人员破译了Apc突变细胞如何获得优于野生型的克隆优势来实现固定。研究人员发现,Apc突变细胞富含编码几种分泌性WNT拮抗剂的转录物,其中Notum表达最高。来自Apc突变细胞的条件培养基以NOTUM依赖性方式抑制野生型类器官的生长。此外,NOTUM分泌的Apc突变体克隆主动抑制周围野生型隐窝细胞的增殖并推动它们的分化,从而在竞争中战胜了来自微环境的隐窝细胞。NOTUM的遗传或药理学抑制消除了Apc突变细胞扩大和形成肠腺瘤的能力。研究人员将NOTUM确定为突变固定早期阶段的关键介导者,这能够靶向用于恢复野生型细胞的竞争力,并为处于结直肠癌的高风险人群提供了预防策略。

据了解,抑癌基因APC是结直肠癌中最常见的突变基因。肠道干细胞中Apc的缺失通过增加WNT信号传导来驱使小鼠腺瘤的形成,但WNT配体分泌的减少增加了Apc突变肠道干细胞定殖隐窝(也称为固定)的能力。

附:英文原文

Title: NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

Author: Dustin J. Flanagan, Nalle Pentinmikko, Kalle Luopajrvi, Nicky J. Willis, Kathryn Gilroy, Alexander P. Raven, Lynn Mcgarry, Johanna I. Englund, Anna T. Webb, Sandra Scharaw, Nadia Nasreddin, Michael C. Hodder, Rachel A. Ridgway, Emma Minnee, Nathalie Sphyris, Ella Gilchrist, Arafath K. Najumudeen, Beatrice Romagnolo, Christine Perret, Ann C. Williams, Hans Clevers, Pirjo Nummela, Marianne Lhde, Kari Alitalo, Ville Hietakangas, Ann Hedley, William Clark, Colin Nixon, Kristina Kirschner, E. Yvonne Jones, Ari Ristimki, Simon J. Leedham, Paul V. Fish, Jean-Paul Vincent, Pekka Katajisto, Owen J. Sansom

Issue&Volume: 2021-06-02

Abstract: The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer. NOTUM from Apc-mutant cells acts as a key mediator during the early stages of mutation fixation and drives the formation of intestinal adenomas.

DOI: 10.1038/s41586-021-03525-z

Source: https://www.nature.com/articles/s41586-021-03525-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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