Spatial Dynamics of Tumor Cell Plasticity in Lung Adenocarcinoma Revealed by Region-Specific Single Cell Transcriptomics

Tumor cell plasticity plays a key role in the progression of malignant neoplasms and therapy resistance, yet its spatial dynamics remain poorly understood. This study investigates the spatial distribution of epithelial–mesenchymal transition (EMT) and stemness, and their prognostic relevance in lung adenocarcinoma (LUAD). Single-cell RNA sequencing was performed on 10 tumor fragments from three regions (core, core-adjacent, and edge) of a single LUAD using a SURFSeq 5000 platform. Stemness potential was identified by CytoTRACE2, EMT by UCell and the Hallmark_epithelial_mesenchymal_transition signature, and tumor cells associated with disease prognosis by Scissor. LUAD displayed pronounced spatial heterogeneity of tumor cell plasticity. Stemness potential was heightened at the edge, while EMT was most prominent in the core. The correlation between EMT and stemness was slightly higher at the edge, though it remained negligible (R = 0.17, p = 5.5e−7). Higher EMT scores were observed in tumor cells associated with poor overall survival (r = 0.433, p < 2e−16), whereas stemness was prevalent in tumor cells associated with poor progression-free survival (r = 0.251, p = 7.15e−6). Tumor cells associated with poor prognosis were enriched with the MYC-targets v1 signature with PCBP1 and PA2G4 as the top contributing genes. Immunohistochemical data showed that PCBP1 and PA2G4 proteins predominantly localized within tumor cells of LUAD. Taken together, these findings highlight the spatial heterogeneity of tumor cell plasticity features in LUAD and uncover biomarkers associated with poor prognosis. © 2025 Wiley Periodicals LLC.