Abstract 7174: Multiomics analysis of lung adenocarcinoma manifesting as radiological part-solid features in female never-smokers

Abstract Purpose: Early-stage lung adenocarcinomas (LUADs) manifesting as part-solid radiological features have a slowly progressive course to invasive malignancy, but its genomic alterations and tumor microenvironment are poorly understood. Methods: We analyzed eleven part-solid type LUADs from female never-smokers. Whole-exome sequencing and whole-transcriptome analysis were conducted on samples from seven patients. Single-cell RNA sequencing was performed on samples from four patients, and spatial transcriptomics was conducted on a sample from one patient. Results: Both the ground-glass and solid components of LUADs exhibited similar characteristics of malignant cells, sharing mutations and showing no significant differences in tumor mutation burden. Compared to the GG component, the solid component showed up-regulation of epithelial-mesenchymal transition (EMT)-related and hypoxia pathways. We identified a cancer-associated secretory (CAS) cell cluster characterized by the expression of the cancer-related gene CEACAM6. CAS cells showed an increasing trend from normal to tumor regions. Interleukin (IL)-1β+ macrophages, a distinct subtype characterized by a pro-inflammatory M1-dominant gene signature, were abundant in solid components. Spatial transcriptomic analysis revealed that IL-1β+ macrophages and CAS cells were co-localized in specific invasive regions of the solid components, which had elevated EMT and hypoxia signatures. Conclusion: We identified that CAS cells and IL-1β+ macrophages are crucial during the progression from the pre-invasive (GG) to invasive adenocarcinoma (solid component). Targeting CAS cells and IL-1β+ macrophages could be preventive or therapeutic strategies for early LUADs. Citation Format: Junsu Choe, Noeul Kang, Jinyeong Lim, Eun Seop Seo, Mina Hwang, Se-Hoon Lee, Myung-Ju Ahn, Yoon-La Choi, Hong Kwan Kim, Woong-Yang Park, Sang-Won Um. Multiomics analysis of lung adenocarcinoma manifesting as radiological part-solid features in female never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7174.