Abstract 113: An atlas of epithelial cell states and plasticity in lung adenocarcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.113-113
• Main Authors: Han, Guangchun, Sinjab, Ansam, Treekitkarnmongkol, Warapen, Rahal, Zahraa, Liu, Yuejiang, Serrano, Alejandra G., Feng, Jiping, Liang, Ke, Khan, Khaja, Lu, Wei, Hernandez, Sharia, Cao, Xuanye, Dai, Enyu, Liu, Yunhe, Pei, Guangsheng, Hu, Jian, Bolanos, Lorena I. Gomez, Parra, Edwin R., Cascone, Tina, Sepesi, Boris, Moghaddam, Seyed Javad, Scheet, Paul, Negrao, Marcelo V., Heymach, John V., Li, Mingyao, Chen, Jichao, Dubinett, Steven M., Fujimoto, Junya, Solis, Luisa M., Wistuba, Ignacio I., Stevenson, Christopher S., Spira, Avrum, Wang, Linghua, Kadara, Humam
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-113

Understanding cellular processes underlying early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. While most if not all single-cell RNA sequencing (scRNA-seq) studies of lung cancer provided details on immune and stromal states, little insight is drawn to epithelial cells given their paucity (~4%) when performing unbiased scRNA-seq analysis without prior enrichment. Here, we performed in-depth scRNA-seq of enriched (by sorting for EPCAM+) epithelial cell subsets from 16 early-stage LUADs and 47 matching normal lung (NL) tissues. We also studied tissues from the same LUADs and adjacent NL by whole exome sequencing and a subset by high-resolution spatial protein and transcriptome analysis. We also performed scRNA-seq analysis of murine lungs from a human-relevant model of LUAD development following exposure to tobacco carcinogen, including strains with an alveolar type II (AT2) cell-specific lineage reporter. After extensive quality control, we retained 246,102 high quality human epithelial cells which comprised diverse normal alveolar and airway lineages as well as cancer cell populations. Diversity among cancer cells was strongly linked to LUAD oncogenic drivers. KRAS-mutant cancer cells were unique in their transcriptional features, strikingly reduced differentiation, low levels of copy number changes, and increased variability amongst the cells themselves. The local epithelial niche of LUADs, relative to that of NL, was enriched with intermediary cells in lung alveolar differentiation. A subset of these cells displayed elevated KRT8 expression (KRT8+ alveolar cells; KACs), increased plasticity and frequency of KRASG12D mutations, and its gene expression profiles were enriched in lung precancer and LUAD and signified poor survival. Notably, KACs harboring KRAS mutations were only found in the ecosystem of KRAS-mutant LUADs. Murine KACs were evident in lungs of tobacco carcinogen-exposed mice that develop KRAS-mutant LUADs but not in the saline-treated control group. While murine KACs emerged prior to tumor onset, they persisted for months after carcinogen cessation, and like their human counterparts, acquired driver Kras mutations, were poorly differentiated, and harbored KRAS-specific transcriptional programs. Spatial transcriptomics analysis showed that KAC and KRAS signatures were elevated in both murine and human tumors as well as in KACs that were in the local spatial vicinity of the LUADs. Organoids derived from l