Single-cell and spatial transcriptomic analyses reveal the cellular origins and drivers of liver metastasis from pancreatic cancer

Pancreatic cancer is a deadliest malignancy. The most common event of tumor progression in pancreatic cancer is liver metastasis, and current treatments have not produced the desired results. However, the cellular origins and drivers of liver metastasis have yet to be defined. In this study, we identified nine cell clusters in pancreatic cancer via analyzing single-cell transcriptomic profiles. Malignant epithelial cells in liver metastatic group might come from primary tumor subclones with 27 common gene copy number variation. Cell-cell communication demonstrated that malignant epithelial cells were specifically regulated by IL-1, Periostin, and IFN-II signaling pathways and fibroblasts regulated malignant epithelial cells through the Periostin pathway (POSTN-ITGAV/ITGB5). Moreover, we found that 34 differentially expressed genes were highly enriched in PI3K signaling pathway. Next, we constructed a LM index using these 34 genes, and found that pancreatic cancer patients with high-index exhibited a poor prognosis. The immuno-fluorescence staining assay showed that the spatial distance between POSTN and ITGAV was close, and ITGAV protein was expressed in tissue sections of pancreatic cancer patients. Finally, we found that ITGAV was upregulated in PANC-1 cells, and knockdown of ITGAV inhibited the invasion and migration of PANC-1 cells. This study clarified possible cellular origins and driv-ers of LM pancreatic cancer based on the single-cell and spatial transcriptomic profiles, and dis-covered that the ITGAV mRNA and protein were expressed in pancreatic cancer tissue and cells, and the knockdown of ITGAV inhibited the progression of pancreatic cancer.