Spatial transcriptomics uncovers immune-cell plasticity and dedifferentiation signatures in aggressive lung adenocarcinoma subtypes.

Intrinsic genetic alterations and dynamic transcriptional changes contribute to the heterogeneity of solid tumors. Lung adenocarcinoma (LUAD) is characterized by its significant histological, cellular and molecular heterogeneity. The present study aimed to study the spatial transcriptomics of primary LUAD with initial hopes to decipher molecular characteristics of subtype transitions in LUAD progression, offering new insights for novel therapeutic strategies. Spatial transcriptomics libraries were first generated from tumor samples collected from patients with LUAD who underwent surgical resection in The Fourth Hospital of Hebei Medical University in 2022 and were sequenced using Illumina NovaSeq 6000 system. The processed data were analyzed for differential gene expressions and networks, and were annotated according to cell type, spatial ligand-receptor interaction and trajectory inference. Our analysis revealed 34 annotated cell types, with cancer-associated fibroblasts (CAFs) being the most abundant, playing a crucial role in tumor microenvironment remodeling and prognosis. We noted significant spatial correlations between various immune cells and found that different histological subtypes displayed unique cell composition profiles, particularly in the micropapillary subtype, which exhibited higher macrophage proportions and distinct gene expression pathways related to extracellular matrix organization and receptor tyrosine kinase signaling. Additionally, we explored the dedifferentiation states within these subtypes, identifying that region with higher dedifferentiation scores corresponded to increased tumor invasiveness and potential drug resistance. Our findings demonstrate dynamic biological changes and dedifferentiation states of tumor subtypes during the progression process. This study reveals important biological processes in tumor development and may offer valuable guidance for future therapeutic strategies.