An atlas of epithelial cell states and plasticity in lung adenocarcinoma

• 成果类型: Article
• 署名作者: Han, Guangchun; Sinjab, Ansam; Rahal, Zahraa; Lynch, Anne M.; Treekitkarnmongkol, Warapen; Liu, Yuejiang; Serrano, Alejandra G.; Feng, Jiping; Liang, Ke; Khan, Khaja; Lu, Wei; Hernandez, Sharia D.; Liu, Yunhe; Cao, Xuanye; Dai, Enyu; Pei, Guangsheng; Hu, Jian; Abaya, Camille; Gomez-Bolanos, Lorena I.; Peng, Fuduan; Chen, Minyue; Parra, Edwin R.; Cascone, Tina; Sepesi, Boris; Moghaddam, Seyed Javad; Scheet, Paul; Negrao, Marcelo V.; Heymach, John V.; Li, Mingyao; Dubinett, Steven M.; Stevenson, Christopher S.; Spira, Avrum E.; Fujimoto, Junya; Solis, Luisa M.; Wistuba, Ignacio I.; Chen, Jichao; Wang, Linghua; Kadara, Humam
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; University of Pennsylvania; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of California System; University of California Los Angeles; Boston University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6063
• DOI: 10.1038/s41586-024-07113-9
• 发表日期: 2024-04-04
• 关键词: single-cell; differentiation program; bronchial epithelium; cancer; landscape; field; methylation; diversity; EVOLUTION; Mutation

摘要

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention. Analyses of single epithelial cells from early-stage lung adenocarcinoma and normal lung identifies a population of intermediate cells that may have an increased likelihood of transforming to tumour cells after injury such as tobacco exposure.