Fig 2: Construction of intercellular communication networks for PDAC tumors and control samples. A) Bar plot showing the proportion of each cell type in PDAC tumors and control samples. B) Bar plot comparing the quantity and strength of cell‐cell interactions in PDAC tumors and control samples. C,D) Circular diagram illustrating the interaction quantity (C) and intensity (D) between PDAC tumors and control samples. E) Heatmap depicting the differential strength of intercellular interactions. F) Scatter chart visualizing the strength of outgoing and incoming interactions. G) All signaling pathways were ranked based on their differences in the relative information flow within the inferred networks between PDAC tumors and control samples. H) Comparison of the significant ligand‐receptor pairs involved in type 2 ductal cell‐beta cell interactions between PDAC tumors and control samples. I,J) Incoming (I) and outgoing (J) patterns of MDK signaling pathway among cell clusters in PDAC tumors and control samples.

Fig 3: A schematic model of the SP1‐MDK‐SDC4‐Ras signaling axis in PCAND. Unlike T2DM, which is characterized primarily by insulin resistance, PCAND is characterized principally by insulin deficiency caused by tumor‐specific products. SP1 directly regulates MDK expression via binding its promoter in PDAC cells. MDK exerts inhibitory effects on beta cell function by directly binding SDC4 receptor and subsequently upregulating Cav1 to downregulate Ras signaling pathway in beta cells. Two TFs including MafA and Pdx1 are crucial for insulin synthesis and secretion. These two factors are in vitro substrates for ERK1/2, and their expression levels were inhibited by MDK‐SDC4 interactions, leading to insulin deficiency and the development of PCAND.

Fig 4: Pseudotime and single‐cell trajectory analyses of ductal cells in PDAC samples. A) t‐SNE plot showing two sub‐clusters of ductal cells. B) t‐SNE plot illustrating the expression of MDK in two ductal cell clusters. C) Volcano plot depicting differentially expressed genes between type 1 and 2 ductal cells. Red dots represent genes expressed at higher levels in type 2 ductal cells while blue dots represent genes with higher expression levels in type 1 ductal cells. D) GO analysis of genes with higher expression levels in type 2 ductal cells. E) GSEA plot displaying the upregulated signaling pathways in type 2 ductal cells. F) t‐SNE plot of CytoTRACE scores showing the distribution of cell stemness from type 1 to type 2 ductal cells. G) Box plot comparing the CytoTRACE values between type 1 and type 2 ductal cells. H) t‐SNE plot depicting the trajectory of ductal cells using Slingshot. I) Dot plots showing dynamic expression of marker genes of type 1 ductal cells (AMBP), type 2 ductal cells (MUC1) and MDK. J) Heatmap showing two expression patterns of differentially expressed genes along the pseudotime.