Dynamic remodelling of epithelial plasticity in colorectal cancer from single-cell and spatially resolved perspectives.

BACKGROUND: Epithelial compartments play a central role in the progression and metastasis of colorectal cancer (CRC), yet the mechanisms underlying their transcriptional reprogramming across disease stages remain incompletely understood. METHODS: We constructed comprehensive single-cell and spatial transcriptomic atlases encompassing normal colorectal tissue, primary CRC, and liver metastases (LMs), profiling over 200,000 high-quality cells. Specific coexpression modules and transcriptional regulators were identified and spatially mapped. Additionally, the clinical and functional roles of SCAND1 were investigated using western blot, RT-qPCR, and immunohistochemistry in clinical samples, as well as functional assays in CRC cell lines. RESULTS: Distinct coexpression modules were selectively enriched in normal epithelial cells and associated with vesicle transport, ion homeostasis, and barrier function, whereas LM-specific modules were linked to Wnt signalling, ribosome biogenesis, and cell cycle processes. High-CNV epithelial cells exhibited progressive activation of key transcription factors such as CEBPB, E2F, and the AP-1 family, with concurrent suppression of ARGLU1 and MTNR2L8, indicating coordinated remodelling of transcriptional and metabolic programs during metastasis. These changes were spatially validated and correlated with alterations in epithelial composition within the tumour core. Consistently, multiplex immunofluorescence (mIHC) confirmed the expression patterns of CEBPB, ARGLU1, S100A4 and FOSL1, across normal epithelium, CRC, and LM. Notably, SCAND1 was identified as a potential therapeutic target for malignant epithelial plasticity. We demonstrated for the first time that SCAND1 expression is significantly upregulated in CRC patients and is associated with superior diagnostic and prognostic value. Functional experiments revealed that SCAND1 promotes tumour cell proliferation, inhibits apoptosis, and enhances metastatic potential. Furthermore, co-culture of SCAND1-overexpressing tumour cells with T cells showed that SCAND1 overexpression attenuates T cell–mediated cytotoxicity, supporting an additional immune-evasive role. CONCLUSIONS: Our study elucidates the molecular logic of epithelial state transitions during CRC metastasis and underscores the promise of SCAND1 as a novel biomarker and therapeutic target in colorectal cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07380-8.