Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation

Yi-Ing Chen, Chin-Chun Chang, Min-Fen Hsu, Yung-Ming Jeng, Yu-Wen Tien, Ming-Chu Chang, Yu-Ting Chang, Chun-Mei Hu () and Wen-Hwa Lee ()
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Yi-Ing Chen: Genomics Research Center, Academia Sinica
Chin-Chun Chang: Genomics Research Center, Academia Sinica
Min-Fen Hsu: Genomics Research Center, Academia Sinica
Yung-Ming Jeng: National Taiwan University Hospital, Graduate Institute of Pathology, College of Medicine, National Taiwan University
Yu-Wen Tien: National Taiwan University Hospital, College of Medicine, National Taiwan University
Ming-Chu Chang: College of Medicine, National Taiwan University
Yu-Ting Chang: College of Medicine, National Taiwan University
Chun-Mei Hu: Genomics Research Center, Academia Sinica
Wen-Hwa Lee: Genomics Research Center, Academia Sinica

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30638-4

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