Homeostasis limits keratinocyte evolution.
Homeostasis limits keratinocyte evolution.
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DOI：
10.1073/pnas.2006487119
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发表时间：
2022-08-30
影响因子：
11.1
通讯作者：
Anderson, Alexander R. A.
中科院分区：
文献类型：
--
作者：
Schencka, Ryan O.;Kim, Eunjung;Bravo, Rafael R.;West, Jeffrey;Leedham, Simon;Shibata, Darryl;Anderson, Alexander R. A.
人类的皮肤充满了变异，产生了大小不一的亚克隆。这些突变中的一些是与癌症发展和进展有关的驱动突变，由于它们的相对大小，它们似乎处于正选择之下。我们展示了这些驱动程序和非驱动程序的“乘客”突变编码的分裂和损失的组织内使用一个简单的模型结合现实的突变跟踪的历史。使用三维的硅稳态表皮模型，我们揭示了许多突变可能缺乏功能异质性，而是简单地在基底层内的生命早期出现的突变。我们使用我们的模型来揭示驱动突变所传达的功能差异如何在维持稳态的同时导致持久性表型。最近的研究表明，正常的人体组织积累了许多体细胞突变。特别是，人类的皮肤充满了突变，有多个大小不等的亚克隆。驱动突变是频繁的，往往有较大的亚克隆大小，这表明选择。为了开始理解这些复杂的体细胞突变编码的历史，我们将基因组纳入一个简单的基于代理的皮肤细胞模型，其主要指令是稳态。在这个模型中，干细胞的存活是随机的，并且依赖于与基底膜的接近程度。这个简单的稳态皮肤模型概括了观察到的体细胞突变的对数线性分布，其中大多数突变发现于越来越小的亚克隆中，这些亚克隆通常随时间而丢失。因此，中性突变是“乘客”，其命运取决于其干细胞的随机存活，而更大的亚克隆则反映了生命早期获得的突变的存活和传播。如果这些突变（NOTCH1和TP53）在正常皮肤或组织损伤（日光）期间赋予相对较高的持久性，则该模型还可以维持稳态并积累更频繁和更大的驱动亚克隆。因此，一个相对简单的上皮细胞更新模型表明，观察到的乘客和司机体细胞突变如何积累，而不违反正常人体组织中稳态的主要指示。
Human skin is riddled with mutations creating subclones of variable sizes. Some of these mutations are driver mutations, implicated in cancer development and progression, that appear to be under positive selection due to their relative sizes. We show how these driver and nondriver “passenger” mutations encode their history of division and loss within the tissue using a simple model combined with realistic mutation tracking. Using a three-dimensional in silico homeostatic epidermis model, we reveal that many mutations likely lack functional heterogeneity and are, instead, simply those that arise earlier in life within the basal layer. We use our model to reveal how functional differences conveyed by driver mutations could lead to a persistence phenotype while maintaining homeostasis. Recent studies have revealed that normal human tissues accumulate many somatic mutations. In particular, human skin is riddled with mutations, with multiple subclones of variable sizes. Driver mutations are frequent and tend to have larger subclone sizes, suggesting selection. To begin to understand the histories encoded by these complex somatic mutations, we incorporated genomes into a simple agent-based skin-cell model whose prime directive is homeostasis. In this model, stem-cell survival is random and dependent on proximity to the basement membrane. This simple homeostatic skin model recapitulates the observed log-linear distributions of somatic mutations, where most mutations are found in increasingly smaller subclones that are typically lost with time. Hence, neutral mutations are “passengers” whose fates depend on the random survival of their stem cells, where a rarer larger subclone reflects the survival and spread of mutations acquired earlier in life. The model can also maintain homeostasis and accumulate more frequent and larger driver subclones if these mutations (NOTCH1 and TP53) confer relatively higher persistence in normal skin or during tissue damage (sunlight). Therefore, a relatively simple model of epithelial turnover indicates how observed passenger and driver somatic mutations could accumulate without violating the prime directive of homeostasis in normal human tissues.
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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：
16.6
作者：
Lynch MD;Lynch CNS;Craythorne E;Liakath-Ali K;Mallipeddi R;Barker JN;Watt FM
通讯作者：
Watt FM
通过大量测序数据定量癌症中克隆的选择。
影响因子：
30.8
作者：
Williams MJ;Werner B;Heide T;Curtis C;Barnes CP;Sottoriva A;Graham TA
通讯作者：
Graham TA
影响因子：
10.7
作者：
Schenck, Ryan O.;Brosula, Gabriel;West, Jeffrey;Leedham, Simon;Shibata, Darryl;Anderson, Alexander R. A.
通讯作者：
Anderson, Alexander R. A.
影响因子：
11.2
作者：
Kim E;Rebecca V;Fedorenko IV;Messina JL;Mathew R;Maria-Engler SS;Basanta D;Smalley KS;Anderson AR
通讯作者：
Anderson AR