Lactate-associated gene PLAU promotes liver metastasis of pancreatic ductal adenocarcinoma.

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) often recurs as lethal liver metastasis, but the molecular factors that facilitate hepatic colonization remain unclear.

METHODS

Transcriptomic data from 9 primary PDAC tumors and 12 liver metastases (GSE19279 and GSE42952) were integrated with 2420 lactate-related genes (LRGs). Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and survival analysis were employed to identify key genes. Analyzing hub genes using a single-cell dataset (GSE156405). Functional validation of PLAU was performed by shRNA-mediated knockdown, followed by qRT-PCR, Western blot, CCK-8 proliferation, colony formation, Transwell migration assays, and patient-derived organoid models.

RESULTS

A total of 102 LRG-derived DEGs were enriched in cell-motility pathways. PLAU emerged as the only potential prognostic biomarker (HR = 1.78, P = 0.003). Single-cell RNA sequencing localized PLAU to myeloid and malignant clusters. PLAU silencing significantly reduced proliferation, colony, and sphere formation both in vitro and in organoids (P < 0.01).

CONCLUSION

PLAU, a lactate-associated, cell-intrinsic driver of PDAC liver metastasis, represents a promising metabolic-epigenetic target for preventing or treating hepatic relapse.