Multi-omics profiling reveals that Scissor(+) epithelial cells regulate intrahepatic metastasis of HCC via remodeling the metastatic microenvironment.

PURPOSE: Malignancy epithelial cells exhibit considerable heterogeneity in HCC. However, the mechanism of malignant epithelial cells in the early intrahepatic metastasis (IM) remains elusive. Our aim was to identify the specific malignant epithelial cells and uncover the underlying mechanism contributing to the HCC IM. METHODS: Multi-omics were utilized to perform a comprehensive analysis of HCC IM. The heterogeneity of malignant epithelial cells was elucidated through multiply analyses, including Ro/e, Slingshot and Monocle 3 pseudotime analyses. Next, “Scissor” was employed to identify malignant epithelial cell (Scissor(+) epithelial cell). Furthermore, “MIME” was used to establish an IM-associated prognostic signature for calculating Scissor(+) related epithelial score (SRES). Moreover, “CellChat” and “NicheNet” were utilized to identify significant crosstalk between Scissor(+) epithelial cells and various immunosuppressive cells. Finally, Multiplex immunohistochemistry (mIHC), Western blotting and Transwell migration assays were conducted for validation. RESULTS: The heterogeneity landscape of malignant epithelial cells in HCC IM has been identified. Combined with Scissor(+) epithelial cells were enriched in C3, C3 was defined as a high-risk epithelial cluster for metastasis. Notably, EMT-related genes were elevated in Scissor(+) epithelial cells, indicating these cells facilitate HCC IM. Then, six critical high-risk metastasis genes exhibiting higher expression in Scissor(+) epithelial cells were utilized for calculating SRES for HCC patients. HCC patients with higher SRES exhibited significantly unfavourable clinical outcomes compared to those with lower SRES. Meanwhile, our signature exhibited a marked superiority over 39 previously published signatures. Interestingly, Scissor(+) epithelial cells can remodel the metastatic microenvironment by recruiting CD4(+) Treg via CCL20–CCR6 and enriching BCAM(+) Cancer-associated fibroblasts (CAFs) through MDK-SDC2 and MDK-NCL. The spatial position of above cells was revealed by mIHC to validate the potential of crosstalk. Finally, Scissor(+) epithelial cells can recruit more normal fibroblasts and convert them to BCAM(+) CAF via MDK-SDC2 and MDK-NCL. CONCLUSION: Scissor(+) epithelial cells were defined as malignant epithelial cells, which facilitate HCC IM and deteriorate the tumor microenvironment (TME). Then, SRES was established to predict the prognosis of HCC patients. Finally, the mechanisms of Scissor(+) epithelial cells in remodeling the TME have been further elucidated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-025-01147-5.