Computational biology and chemistry · 2026
Lactate-associated gene PLAU promotes liver metastasis of pancreatic ductal adenocarcinoma.
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Liao Xinghe, Zhang Fenglin, Huang Qun, Wu Xiaorui, Zhao Jiangang, Zhou Zhou, Chen Hao, Li Ping
Аннотация
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.
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.