Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
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DOI：
10.1038/s41586-021-03965-7
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发表时间：
2021-10
期刊：
影响因子：
64.8
通讯作者：
Jones PH
中科院分区：
文献类型：
--
作者：
Colom B;Herms A;Hall MWJ;Dentro SC;King C;Sood RK;Alcolea MP;Piedrafita G;Fernandez-Antoran D;Ong SH;Fowler JC;Mahbubani KT;Saeb-Parsy K;Gerstung M;Hall BA;Jones PH
人类上皮组织随着年龄的增长而积累癌症驱动突变，但肿瘤形成仍然罕见。这些突变的积极选择表明它们改变了增殖细胞的行为和适应性。因此，正常的成年组织变成了一个由突变克隆体组成的拼凑体，它们争夺空间和生存，最适合的克隆体通过消除竞争力较弱的邻居来扩大。然而，很少有人知道如何在正常上皮细胞的动态竞争影响早期肿瘤发生。在这里，我们表明，大多数新形成的食管肿瘤是通过与相邻正常上皮中的突变克隆竞争而消除的。我们在食管癌发生的小鼠模型中追踪了新生的、显微镜下的、恶性前肿瘤的命运，发现大多数肿瘤迅速消失，没有肿瘤细胞死亡、增殖减少或抗肿瘤免疫反应的迹象。然而，10天和1岁肿瘤的深度测序显示了对存活肿瘤的选择证据。在转基因小鼠中诱导高度竞争性克隆增加了早期肿瘤去除，而抑制克隆竞争的抑制剂减少了肿瘤丢失。这些结果支持了一个模型，早期肿瘤的生存取决于它们相对于周围正常组织中突变克隆的竞争适应性。正常上皮中的突变克隆在通过细胞竞争清除早期肿瘤中具有意想不到的抗肿瘤作用，从而保持组织完整性。
Human epithelial tissues accumulate cancer-driver mutations with age, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumors in a mouse model of esophageal carcinogenesis, finding most are rapidly lost with no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. However, deep-sequencing of 10-day and 1-year-old tumors showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. These results support a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumors through cell competition, thereby preserving tissue integrity.
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影响因子：
12.3
作者：
Kuilman T;Velds A;Kemper K;Ranzani M;Bombardelli L;Hoogstraat M;Nevedomskaya E;Xu G;de Ruiter J;Lolkema MP;Ylstra B;Jonkers J;Rottenberg S;Wessels LF;Adams DJ;Peeper DS;Krijgsman O
通讯作者：
Krijgsman O
DOI：
10.1126/science.aau3879
发表时间：
2018-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH
通讯作者：
Jones PH
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
64.8
作者：
Moore, Luiza;Leongamornlert, Daniel;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
21.3
作者：
通讯作者：
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