Integrated bulk, single-cell and spatial transcriptomic analyses identify KIFC1 as a driver of malignant progression in lung adenocarcinoma.

BACKGROUND: Kinesin family member C1 (KIFC1), a minus-end-directed kinesin motor protein, has been implicated in centrosome clustering and tumor progression. However, its cellular distribution and potential roles in malignant cell plasticity and tumor microenvironment-associated signaling in lung adenocarcinoma (LUAD) remain incompletely understood.

METHODS: TCGA-LUAD, single-cell RNA sequencing (E-MTAB-6149), and spatial transcriptomic data (GSE307534) were analyzed to characterize KIFC1 expression patterns and clinical significance. Functional enrichment, cell-cell communication, virtual-knockout, and cell-state trajectory analyses were performed to investigate KIFC1-associated biological programs. Drug sensitivity was computationally estimated, with particular attention to erlotinib, and exploratory molecular docking was performed. The effects of KIFC1 knockdown on LUAD cell proliferation, migration, invasion, tumorsphere formation, and epithelial-mesenchymal transition (EMT) were evaluated in vitro.

RESULTS: KIFC1 was significantly overexpressed in LUAD and was associated with unfavorable overall survival. Single-cell and spatial transcriptomic analyses showed that KIFC1 was predominantly expressed in malignant epithelial cells and increased across advanced malignant cell states and pathological stages. KIFC1-high malignant cells exhibited enhanced cell-cycle activity, stemness, and EMT programs. Computational analyses further associated these cells with MIF- and SPP1-related intercellular signaling. KIFC1 knockdown significantly inhibited proliferation, colony formation, tumorsphere formation, migration, invasion, and EMT. Drug-response prediction indicated a higher estimated erlotinib IC50 in KIFC1-high tumors, suggesting potentially reduced responsiveness that requires experimental validation.

CONCLUSION: KIFC1 is associated with malignant progression, stemness, and EMT in LUAD. Computational analyses additionally suggest a potential relationship between KIFC1-associated malignant states and tumor microenvironmental signaling, supporting its value as a prognostic biomarker and potential therapeutic target.