Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis.
Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis.
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斑马鱼成像显示，在原发肿瘤发生中，TP53突变将癌基因诱导的衰老从抑制者转换为驱动者。
DOI：
10.1038/s41467-022-29061-6
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发表时间：
2022-03-18
影响因子：
16.6
通讯作者：
Ishitani T
中科院分区：
文献类型：
--
作者：
Haraoka Y;Akieda Y;Nagai Y;Mogi C;Ishitani T
大多数肿瘤被认为是通过致癌细胞产生，然后发生额外的突变而产生的。新的致癌细胞如何通过获得额外的突变来引发肿瘤发生仍然不清楚。我们发现，一个额外的TP 53突变刺激原发性肿瘤的发生，通过切换癌基因诱导的衰老从肿瘤抑制因子的驱动程序。斑马鱼成像显示，具有RasG 12 V突变的新出现的致癌细胞变得衰老并从上皮细胞中消除，这通过向RasG 12 V细胞中添加TP 53功能获得性突变（TP 53 R175 H）来防止。存活的RasG 12 V-TP 53 R175 H双突变细胞衰老并分泌衰老相关分泌表型（SASP）相关的炎症分子，将邻近的正常细胞转化为分泌SASP因子的衰老细胞，产生异质性肿瘤样细胞团。我们确定了致癌细胞的行为，可能会控制最初的人类肿瘤发生的步骤。Ras和TP 53突变和细胞衰老在人类肿瘤中经常被检测到;在人类肿瘤发生的初始步骤中可能发生类似的转换。目前还不清楚单个致癌细胞如何引发肿瘤发生。在这里，作者使用斑马鱼幼虫皮肤作为模型可视化了这种行为，并表明RasG 12 V致癌细胞通过癌基因衰老被消除，而p53中的功能突变的获得将这种行为从肿瘤抑制改变为肿瘤促进。
Most tumours are thought to arise through oncogenic cell generation followed by additional mutations. How a new oncogenic cell primes tumorigenesis by acquiring additional mutations remains unclear. We show that an additional TP53 mutation stimulates primary tumorigenesis by switching oncogene-induced senescence from a tumour suppressor to a driver. Zebrafish imaging reveals that a newly emerged oncogenic cell with the RasG12V mutation becomes senescent and is eliminated from the epithelia, which is prevented by adding a TP53 gain-of-function mutation (TP53R175H) into RasG12V cells. Surviving RasG12V-TP53R175H double-mutant cells senesce and secrete senescence-associated secretory phenotype (SASP)-related inflammatory molecules that convert neighbouring normal cells into SASP factor-secreting senescent cells, generating a heterogeneous tumour-like cell mass. We identify oncogenic cell behaviours that may control the initial human tumorigenesis step. Ras and TP53 mutations and cellular senescence are frequently detected in human tumours; similar switching may occur during the initial step of human tumorigenesis. It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting.
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