NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
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来自APC突变细胞的NOTUM使克隆竞争偏向于引发癌症。
DOI：
10.1038/s41586-021-03525-z
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发表时间：
2021-06
期刊：
影响因子：
64.8
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Flanagan DJ;Pentinmikko N;Luopajärvi K;Willis NJ;Gilroy K;Raven AP;Mcgarry L;Englund JI;Webb AT;Scharaw S;Nasreddin N;Hodder MC;Ridgway RA;Minnee E;Sphyris N;Gilchrist E;Najumudeen AK;Romagnolo B;Perret C;Williams AC;Clevers H;Nummela P;Lähde M;Alitalo K;Hietakangas V;Hedley A;Clark W;Nixon C;Kirschner K;Jones EY;Ristimäki A;Leedham SJ;Fish PV;Vincent JP;Katajisto P;Sansom OJ
APC肿瘤抑制基因是结直肠癌中最常见的突变基因。肠干细胞（ISC）中Apc的丧失通过增加Wnt信号传导驱动小鼠中的腺瘤形成，但减少的Wnt-配体分泌令人惊讶地增加Apc突变型ISC定殖隐窝（固定）的能力。在这里，我们研究了APC突变细胞如何获得比野生型对应物的克隆优势，以实现固定。我们发现，APC突变细胞富含编码几种分泌的Wnt拮抗剂的转录本，Notum是最高表达的。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突变克隆积极抑制周围野生型隐窝细胞的增殖，并驱动其分化，从而在竞争中击败它们。重要的是，Notum的遗传或药理学抑制消除了APC突变细胞扩增和形成肠腺瘤的能力。总而言之，我们将Notum确定为突变固定早期阶段的关键介体，可以有针对性地恢复野生型细胞竞争力，从而为高危患者提供新的预防策略。
The APC tumour suppressor is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells (ISCs) drives adenoma formation in mice via increased Wnt signalling , but reduced Wnt-ligand secretion surprisingly increases the ability of Apc-mutant ISCs to colonise a crypt (fixation) . Here, we investigate how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We find that Apc-mutant cells are enriched for transcripts encoding several secreted Wnt antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppresses the growth of wild-type organoids in a Notum-dependent manner. Furthermore, Notum-secreting Apc-mutant clones actively inhibit the proliferation of surrounding wild-type crypt cells and drive their differentiation, thereby outcompeting them from the niche. Importantly, genetic or pharmacological inhibition of Notum abrogates the ability of Apc-mutant cells to expand and form intestinal adenomas. Taken together, we identify Notum as a key mediator during the early stages of mutation fixation, which can be targeted to restore wild-type cell competitiveness, thus, offering novel preventative strategies for high-risk patients.
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影响因子：
45.3
作者：
Midgley, Rachel S.;McConkey, Christopher C.;Kerr, David J.
通讯作者：
Kerr, David J.
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
64.5
作者：
Moreno, E;Basler, K
通讯作者：
Basler, K
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans