An atlas of epithelial cell states and plasticity in lung adenocarcinoma

Guangchun Han(The University of Texas MD Anderson Cancer Center), Ansam Sinjab(The University of Texas MD Anderson Cancer Center), Zahraa Rahal(The University of Texas MD Anderson Cancer Center), Anne M. Lynch(The University of Texas MD Anderson Cancer Center), Warapen Treekitkarnmongkol(The University of Texas MD Anderson Cancer Center), Yuejiang Liu(The University of Texas MD Anderson Cancer Center), Alejandra G. Serrano(The University of Texas MD Anderson Cancer Center), Jiping Feng(The University of Texas MD Anderson Cancer Center), Ke Liang(The University of Texas MD Anderson Cancer Center), Khaja Khan(The University of Texas MD Anderson Cancer Center), Wei Lü(The University of Texas MD Anderson Cancer Center), Sharia Hernandez(The University of Texas MD Anderson Cancer Center), Yunhe Liu(The University of Texas MD Anderson Cancer Center), Xuanye Cao(The University of Texas MD Anderson Cancer Center), Enyu Dai(The University of Texas MD Anderson Cancer Center), Guangsheng Pei(The University of Texas MD Anderson Cancer Center), Jian Hu(University of Pennsylvania), Camille Abaya(The University of Texas MD Anderson Cancer Center), Lorena I. Gomez-Bolanos(The University of Texas MD Anderson Cancer Center), Fuduan Peng(The University of Texas MD Anderson Cancer Center), Minyue Chen(The University of Texas MD Anderson Cancer Center), Edwin R. Parra(The University of Texas MD Anderson Cancer Center), Tina Cascone(The University of Texas MD Anderson Cancer Center), Boris Sepesi(The University of Texas MD Anderson Cancer Center), Seyed Javad Moghaddam(The University of Texas MD Anderson Cancer Center), Paul Scheet(The University of Texas MD Anderson Cancer Center), Marcelo V. Negrão(The University of Texas MD Anderson Cancer Center), John V. Heymach(The University of Texas MD Anderson Cancer Center), Mingyao Li(University of Pennsylvania), Steven M. Dubinett(University of California, Los Angeles), Christopher S. Stevenson(Johnson & Johnson (United States)), Avrum Spira(Boston University), Junya Fujimoto(The University of Texas MD Anderson Cancer Center), Luisa M. Solis(The University of Texas MD Anderson Cancer Center), Ignacio I. Wistuba(The University of Texas MD Anderson Cancer Center), Jichao Chen(The University of Texas MD Anderson Cancer Center), Linghua Wang(The University of Texas MD Anderson Cancer Center), Humam Kadara(The University of Texas MD Anderson Cancer Center)
Nature
February 28, 2024
10.1038/s41586-024-07113-9
Cited by 155Open Access
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Abstract

Abstract Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies 1 . 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.

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