Department of medical physics and biomedical engineering, UCL, Gower Street, London WC1E 6BT, UK.
MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
J R Soc Interface. 2021 Oct;18(183):20210607. doi: 10.1098/rsif.2021.0607. Epub 2021 Oct 13.
During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are and , both of which are also recurrently mutated in cancers of these tissues. From observations taken in human and mouse epithelia, we find that clones carrying and pathway mutations have different clone dynamics which can be explained by their different responses to local cell crowding. mutant clone growth in mouse epidermis approximates a logistic curve, but feedbacks responding to local crowding are required to maintain tissue homeostasis. We go on to show that the observed ability of pathway mutant cells to displace the wild-type population in the mouse oesophageal epithelium reflects a local density feedback that affects both mutant and wild-type cells equally. We then show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets and are suggestive of a putative mechanism to constrain these cancer-associated mutants.
随着衰老，正常上皮组织逐渐积累携带突变的克隆，这些突变使突变细胞的适应性超过野生型细胞。这些突变体广泛传播到组织中，但尽管如此，上皮细胞的细胞内平衡和功能完整性仍得以维持。在人类皮肤和食道中最常发生突变的两个基因是 和 ，这两个基因在这些组织的癌症中也经常发生突变。从对人类和小鼠上皮组织的观察中，我们发现携带 和 通路突变的克隆具有不同的克隆动力学，这可以通过它们对局部细胞拥挤的不同反应来解释。在小鼠表皮中， 突变体克隆的生长近似于逻辑曲线，但需要反馈来响应局部拥挤以维持组织内平衡。我们继续表明，在小鼠食道上皮中观察到的 通路突变体细胞取代野生型细胞的能力反映了一种局部密度反馈，这种反馈对突变体细胞和野生型细胞都有同等影响。然后，我们展示了这些不同的反馈如何与人类数据集观察到的突变分布一致，并暗示了一种可能的机制来限制这些与癌症相关的突变体。
