Pancreatic ductal adenocarcinoma (PDAC) is characterized by an asymptomatic disease course, high mortality rate, and resistance to conventional cancer treatments in advanced stage. However, membrane proteins are underexplored as potential therapeutic targets in metastatic PDAC for molecular-targeted therapy. To address these hurdles, we extracted and profiled the membrane proteins in both metastatic PDAC AsPC-1 and SW1990 cell lines using the LCMS/ MS approach, followed by pathway analysis with STRING and REACTOME bioinformatics databases. Based on our findings, both AsPC-1 and SW1990 cell lines shared seven membrane and membrane-associated proteins that related to cancer invasion, including annexin A2 (ANXA2), vimentin (VIM), keratin type I cytoskeletal 18 (KRT18), keratin type I cytoskeletal 19 (KRT19), keratin type II cytoskeletal 8 (KRT8), actin cytoplasmic 2 (ACTG1), and plectin (PLEC). Meanwhile, we also identified another two membrane-associated proteins that related to the metastasis event in the SW1990 cell line, namely galectin-1 (LGALS1) and alpha-actinin-1 (ACTN1). Our GO enrichment analysis results from STRING indicated that these identified proteins are highly interconnected and play essential roles in cancer invasion. They often act collectively and synergistically to modulate the cytoskeletal network within the cell to facilitate cancer invasion. Additionally, we also managed to identify both cell lines shared nine enriched pathways that related to carcinogenesis. Among nine enriched pathways, the collagen formation (R-HSA-1474290) is particularly noteworthy. On top of that, we identified another two enriched pathways that related to the tumour formation in the AsPC-1 cell line, namely the metabolism of serotonin (R-HSA-380612) and assembly of collagen fibrils and other multimeric structures (R-HSA-2022090). As for the SW1990 cell line, another three enriched pathways that related to cancer progression were determined, namely cell recruitment (pro-inflammatory response) (R-HSA-9664424), interleukin-12 signalling (R-HSA-9020591) and cell surface interactions at the vascular wall (R-HSA-202733). In conclusion, our study provides valuable insights into key membrane and membrane-associated proteins, and enriched pathways involved in PDAC invasion and metastasis. These findings contribute to a deeper understanding of PDAC molecular mechanisms and may aid in the development of targeted therapies for metastatic PDAC in the future.