Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties
Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties
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DOI：
10.1038/s41467-020-16245-1
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发表时间：
2020-05-11
影响因子：
16.6
通讯作者：
Oshima, Masanobu
中科院分区：
文献类型：
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作者：
Nakayama, Mizuho;Hong, Chang Pyo;Oshima, Masanobu
错义型突变体p53通过功能获得（GOF）机制发挥促肿瘤作用。此外，在癌细胞中广泛发现因杂合性缺失（LOH）而导致的野生型 TP53 缺失。然而，TP53 GOF 突变和 LOH 协同诱导的恶性进展仍知之甚少。在这里，我们发现，当移植杂合 Trp53 突变细胞 (AKTP(+/M)) 时，携带 Trp53 GOF 突变和 LOH (AKTP(M/LOH)) 的小鼠肠道肿瘤在转移灶中富集。我们发现 Trp53 LOH 是休眠细胞存活和癌细胞克隆扩增所必需的。此外，与AKTP(Null)和AKTP(+/M)细胞相比，AKTP(M/LOH)细胞显示出增强的体内肿瘤启动能力。 RNAseq 分析表明，炎症和生长因子/MAPK 通路在 AKTP(M/LOH) 细胞中被特异性激活，而干细胞特征在 AKTP(M/LOH) 和 AKTP(Null) 细胞中均上调。这些结果表明TP53/Trp53 LOH通过激活不同的途径组合促进TP53/Trp53 GOF突变驱动的转移。突变型 p53 (GOF) 的功能获得和野生型 p53 (LOH) 的丧失均与癌症独立相关。在这里，作者表明 LOH 通过增加肿瘤启动能力和转移来促进 GOF 肿瘤发生。
Missense-type mutant p53 plays a tumor-promoting role through gain-of-function (GOF) mechanism. In addition, the loss of wild-type TP53 through loss of heterozygosity (LOH) is widely found in cancer cells. However, malignant progression induced by cooperation of TP53 GOF mutation and LOH remains poorly understood. Here, we show that mouse intestinal tumors carrying Trp53 GOF mutation with LOH (AKTP(M/LOH)) are enriched in metastatic lesions when heterozygous Trp53 mutant cells (AKTP(+/M)) are transplanted. We show that Trp53 LOH is required for dormant cell survival and clonal expansion of cancer cells. Moreover, AKTP(M/LOH) cells show an increased in vivo tumor-initiating ability compared with AKTP(Null) and AKTP(+/M) cells. RNAseq analyses reveal that inflammatory and growth factor/MAPK pathways are specifically activated in AKTP(M/LOH) cells, while the stem cell signature is upregulated in both AKTP(M/LOH) and AKTP(Null) cells. These results indicate that TP53/Trp53 LOH promotes TP53/Trp53 GOF mutation-driven metastasis through the activation of distinct pathway combination. Both gain-of-function of mutant p53 (GOF) and loss of wild-type p53 (LOH) are independently associated with cancer. Here, the authors show that LOH promotes GOF tumourigenesis by increasing tumor-initiating ability and metastasis.