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- Title
Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation.
- Authors
Chen, Yi-Ing; Chang, Chin-Chun; Hsu, Min-Fen; Jeng, Yung-Ming; Tien, Yu-Wen; Chang, Ming-Chu; Chang, Yu-Ting; Hu, Chun-Mei; Lee, Wen-Hwa
- 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. Direct contact between tumour cells and fibroblasts influences tumour cell behaviour. Here the authors show that pancreatic cancer cells and fibroblasts directly interact via homophilic ATP1A1 binding, which induces fibroblasts to secrete activin A to promote epithelial-mesenchymal transition of tumour cells and myofibroblast activation.
- Subjects
MYOFIBROBLASTS; FIBROBLASTS; CELL aggregation; ACTIVIN; CELL communication; PANCREATIC duct; EPITHELIAL-mesenchymal transition; PANCREATIC tumors
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30638-4