An atlas of epithelial cell states and plasticity in lung adenocarcinoma

Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M. Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G. Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D. Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I. Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R. Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V. Negrao, John V. Heymach, Mingyao Li, Steven M. Dubinett, Christopher S. Stevenson, Avrum E. Spira, Junya Fujimoto, Luisa M. Solis, Ignacio I. Wistuba, Jichao Chen (), Linghua Wang () and Humam Kadara ()
Additional contact information
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 Lu: The University of Texas MD Anderson Cancer Center
Sharia D. 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. Negrao: 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: The University of California Los Angeles
Christopher S. Stevenson: Lung Cancer Initiative at Johnson & Johnson
Avrum E. Spira: Lung Cancer Initiative at Johnson & Johnson
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, 2024, vol. 627, issue 8004, 656-663

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07113-9

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