p53 在肺癌抑制过程中调控 AT1 分化程序

SCI

25 July 2023

p53 governs an AT1 differentiation programme in lung cancer suppression 

（Nature, IF: 64.8）

Alyssa M.Kaiser、Alberto Gatto、Kathryn J.Hanson、Richard L.Zhao、Nitin Raj、Michael G.Ozawa、JoséA.Seoane、Kathry T.Bieging-Rolett、Mengxing Wang、Irene Li、Winston L.Trope、Douglas Z.Liou、Joseph B.Shrager、Sylviritis、Aaron M.Newman、Capucine Van Rechem & Laura D.Attardi

CORRESPONDENCE TO: attardi@stanford.edu

Lung cancer is the leading cause of cancer deaths worldwide. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury. 

肺癌是全球癌症死亡的主要原因。50%的肺腺癌（LUADs）会发生肿瘤抑制基因 TP53 的突变，这与预后不良有关，但p53如何抑制 LUAD 的发展仍是一个谜。本文显示p53通过调节细胞状态来抑制LUAD，特别是1 型肺泡上皮细胞（AT1）分化。利用肺泡 2 型细胞（AT2）中表达致癌基因Kras和无效、野生型或高畸变Trp53等位基因的小鼠，我们观察到p53对LUAD的启动和进展有不同程度的影响。LUAD细胞的RNA测序和ATAC测序发现，在体内肿瘤抑制过程中，p53通过直接DNA结合、染色质重塑和诱导AT1细胞特征基因，诱导AT1分化程序。单细胞转录组学分析表明，在LUAD进化过程中，p53通过在过渡细胞状态中的作用促进AT1分化，这种状态类似于肺泡损伤修复过程中AT2到AT1细胞分化的短暂中间状态。值得注意的是，p53失活会导致这些过渡癌细胞不适当地持续存在，并伴随着生长信号的上调和肺系特征的分化，这些特征与LUAD的进展有关。对Trp53野生型和Trp53缺失型小鼠的分析表明，p53 还能通过调节AT2细胞的自我更新和促进过渡性细胞分化为AT1细胞来指导损伤后的肺泡再生。总之，这些发现阐明了p53介导的 LUAD抑制机制，其中p53主导肺泡分化，并表明肿瘤抑制反映了p53在协调损伤后组织修复中的基本作用。