小柯机器人

美国斯坦福大学Laura D. Attardi小组发现，p53在肺癌抑制过程中调控AT1分化程序。2023年7月19日，《自然》杂志在线发表了这项成果。

研究人员表明，p53通过调节细胞状态，特别是通过促进肺泡1型（AT1）分化来抑制肺腺癌（LUAD）。研究人员利用在肺泡2型（AT2）细胞中表达致癌Kras和无效、野生型或高畸形Trp53等位基因的小鼠，并观察到p53对LUAD启动和进展的分级效应。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演化过程中，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还通过调节AT2细胞自我更新和促进过渡细胞分化为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。

据悉，肺癌是全球癌症死亡的主要原因。50%的LUAD会发生肿瘤抑制基因TP53的突变，并与预后不良有关，但p53如何抑制LUAD的发展仍是一个谜。

附：英文原文

Title: p53 governs an AT1 differentiation programme in lung cancer suppression

Author: Kaiser, Alyssa M., Gatto, Alberto, Hanson, Kathryn J., Zhao, Richard L., Raj, Nitin, Ozawa, Michael G., Seoane, Jos A., Bieging-Rolett, Kathryn T., Wang, Mengxiong, Li, Irene, Trope, Winston L., Liou, Douglas Z., Shrager, Joseph B., Plevritis, Sylvia K., Newman, Aaron M., Van Rechem, Capucine, Attardi, Laura D.

Issue&Volume: 2023-07-19

Abstract: Lung cancer is the leading cause of cancer deaths worldwide1. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1,2,3,4, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type2 (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.

DOI: 10.1038/s41586-023-06253-8

Source: https://www.nature.com/articles/s41586-023-06253-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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