美国耶鲁大学Valentina Greco等研究人员合作发现，损伤阻止马赛克皮肤中Ras突变体细胞的扩张。相关论文于2023年6月21日在线发表在《自然》杂志上。

研究人员表明，在受伤后，野生型细胞会抑制由致癌Ras诱导的异常生长。Hras^G12V/+和Kras^G12D/+细胞在未受伤的马赛克组织中竞争野生型细胞，但由于增殖的野生型细胞的比例增加，它们的扩张在受伤后被阻止。从机制上讲，与Hra^sG12V/+细胞不同，野生型细胞对EGFR配体的自分泌和旁分泌有反应，这种对EGFR途径的不同激活解释了损伤修复期间的竞争转换。通过药物或遗传方法抑制表皮生长因子受体信号，减少了受伤后分裂的野生型细胞的比例，导致Hras^G12V/+细胞的扩张。通过细胞周期抑制因子p21的组成性缺失增加野生型细胞的增殖，抵消了Hras^G12V/+细胞的扩张，即使在没有损伤的情况下也是如此。因此，在遗传性马赛克的皮肤中，损伤在致癌细胞和野生型细胞之间的竞争平衡中起着转换作用。

据介绍，健康的皮肤是由野生型和突变型克隆组成的马赛克。虽然损伤可以与突变的Ras家族蛋白合作，促进肿瘤的发生，但在基因镶嵌的皮肤中的后果尚不清楚。

附：英文原文

Title: Injury prevents Ras mutant cell expansion in mosaic skin

Author: Gallini, Sara, Annusver, Karl, Rahman, Nur-Taz, Gonzalez, David G., Yun, Sangwon, Matte-Martone, Catherine, Xin, Tianchi, Lathrop, Elizabeth, Suozzi, Kathleen C., Kasper, Maria, Greco, Valentina

Issue&Volume: 2023-06-21

Abstract: Healthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3,4,5,6,7,8,9,10,11,12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.

DOI: 10.1038/s41586-023-06198-y

Source: https://www.nature.com/articles/s41586-023-06198-y