Metabolic Reprogramming Promotes Metastasis of Acidosis-Adapted Pancreatic Ductal Adenocarcinoma Cells Via AMPK/YAP/MMP1 Axis

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Acidic microenvironment, namely acidosis, is closely related to cancer development and progression, but the regulatory mechanism remains to be elucidated. Methods We generated acidosis-adapted PDAC cells (PANC-1 and SW1990) by continuously culturing under pH 6.5 medium. Metabonomic assay (LC-MS and LC-MS) was used to detect the metabolites. Transcriptomic microarray was applied to reveal the gene expression profile. The in vivo metastatic potential was assessed by tail vein injection. Wound healing assay and transwell assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation were performed to determine cell proliferation. Flow cytometry was used to test cell cycle and apoptosis. Results These acidosis-adapted PDAC cells had stronger invasion and migration ability, accompanied by increased EMT markers expression. In addition, the proliferation rate of acidosis-adapted PDAC cells increased while apoptosis decreased under acidic medium. Metabonomic analysis showed that the glycolysis and AMP was decreased, and ATP was increased in acidosis-adapted cells. The metabolic shift led to the inactivation of AMPK. Transcriptomic analysis revealed that the differentially expressed genes in acid-adapted cells were enriched in extracellular matrix modification, Hippo signaling and others. MMP1, a matrix metalloproteinase, was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway. Knockdown of MMP1 significantly reduced invasion and metastasis capacity of acidosis-adapted cells. The AMPK activator MK8722 could reduce both YAP and MMP1 level in acidosis-adapted PDAC cells. Conclusion Altogether, the present study showed that the metabolic reprogramming towards elevated ATP production promotes invasion and metastasis of acidosis-adapted PDAC cells via depressing AMPK/Hippo signaling, thus upregulating MMP1.