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

Author

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  • Yi-Ing Chen

    (Genomics Research Center, Academia Sinica)

  • Chin-Chun Chang

    (Genomics Research Center, Academia Sinica
    Master Program for Cancer Biology and Drug Discovery, China Medical University and 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
    National Taiwan University Hospital)

  • Yu-Ting Chang

    (College of Medicine, National Taiwan University
    National Taiwan University Hospital)

  • Chun-Mei Hu

    (Genomics Research Center, Academia Sinica)

  • Wen-Hwa Lee

    (Genomics Research Center, Academia Sinica
    Drug Development Center, China Medical University
    University of California)

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.

Suggested Citation

  • Yi-Ing Chen & Chin-Chun Chang & Min-Fen Hsu & Yung-Ming Jeng & Yu-Wen Tien & Ming-Chu Chang & Yu-Ting Chang & Chun-Mei Hu & Wen-Hwa Lee, 2022. "Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30638-4
    DOI: 10.1038/s41467-022-30638-4
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    References listed on IDEAS

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    1. Mateusz S. Wietecha & Marco Pensalfini & Michael Cangkrama & Bettina Müller & Juyoung Jin & Jürgen Brinckmann & Edoardo Mazza & Sabine Werner, 2020. "Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    2. Kristina Anderson & Christoph Lutz & Frederik W. van Delft & Caroline M. Bateman & Yanping Guo & Susan M. Colman & Helena Kempski & Anthony V. Moorman & Ian Titley & John Swansbury & Lyndal Kearney & , 2011. "Genetic variegation of clonal architecture and propagating cells in leukaemia," Nature, Nature, vol. 469(7330), pages 356-361, January.
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