Identification of homophilic ATP1A1 interaction between tumor cells and fibroblasts

Tumor cells with diverse phenotype 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. Here, we observed enrichment of myofibroblasts in juxta-tumoral position, where tumor cells gain epithelial-mesenchymal transition for invasion, that correlated with worsened prognosis in PDAC patients. Direct cell-cell contacts as forming heterocellular aggregates between fibroblasts and tumor cells were detected in primary pancreatic tumors and circulating tumor microemboli. Mechanistically, the overexpressed ATP1A1 of tumor cells binds to and reorganizes ATP1A1 of fibroblasts inducing calcium oscillations, NF-κB activation, and activin A secretion. Consequentially, either silencing ATP1A1 expression or neutralizing activin A secretion suppresses tumor invasion and colonization. Taken together, these results elucidate the mechanic interplay between tumor cells and the bound fibroblasts in PDAC progression, and provide opportunities for potential therapeutic strategy against tumor metastasis by blocking such interaction.