Tumor cells with diverse phenotypes and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. In the present study, we observe enrichment of myofibroblasts in a juxta-tumoral position with tumor cells undergoing epithelial-mesenchymal transition (EMT) that facilitates invasion and correlates with a worse clinical prognosis in PDAC patients. Direct cell-cell contacts forming heterocellular aggregates between fibroblasts and tumor cells are detected in primary pancreatic tumors and circulating tumor microemboli (CTM). Mechanistically, ATP1A1 overexpressed in tumor cells binds to and reorganizes ATP1A1 of fibroblasts that induces calcium oscillations, NF-κB activation, and activin A secretion. Silencing ATP1A1 expression or neutralizing activin A secretion suppress tumor invasion and colonization. Taken together, these results elucidate the direct interplay between tumor cells and bound fibroblasts in PDAC progression, thereby providing potential therapeutic opportunities for inhibiting metastasis by interfering with these cell-cell interactions.

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