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

Lung adenocarcinomas (LUADs) with part-solid radiological features exhibit slow progression to invasive malignancy; however, the key genomic alterations driving this progression remain poorly understood. We conducted a multiomics analysis of four components (distant and adjacent normal lung and solid [S] and ground-glass [GG] components) of part-solid-type LUADs in female never-smokers. Although GG and S components displayed similar mutational profiles, epithelial–mesenchymal transition and hypoxia pathways were significantly upregulated in the S component. Using single-cell RNA sequencing, we identified a novel cancer-associated secretory (CAS) cell population (SCGB3A2/CEACAM6+). The proportion of CAS cells and interleukin (IL)-1β+ macrophages showed a significant upward trend toward the S component. Spatial transcriptomic analysis revealed that IL-1β+ macrophages and CAS cells co-localized in invasive regions of the tumor. In conclusion, CAS cells and IL-1β+ macrophages play crucial roles in the progression from preinvasive to invasive LUADs, positioning them as promising targets for cancer prevention and therapeutic strategies. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on lung adenocarcinoma (LUAD) samples from seven female, never-smoker patients with part-solid radiological features. For each patient, three distinct regions were analyzed: distant normal lung (DN), ground-glass component (GG), and solid component (S), resulting in a total of 18 samples for bulk sequencing analysis.In addition, single-cell RNA sequencing (scRNA-seq) was conducted on four female, never-smoker patients using the 10X Genomics Chromium platform. Four regions were analyzed for each patient: distant normal lung (DN), adjacent normal lung (AN), ground-glass component (GG), and solid component (S), leading to a total of 16 single-cell RNA-seq samples. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************