Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells

Chen-Chi Liu, Shih-Pei Lin, Han-Shui Hsu, Shung-Haur Yang, Chiu-Hua Lin, Muh-Hwa Yang, Mien-Chie Hung and Shih-Chieh Hung ()
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Chen-Chi Liu: Institute of Clinical Medicine, National Yang-Ming University
Shih-Pei Lin: Institute of Clinical Medicine, National Yang-Ming University
Han-Shui Hsu: Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University
Shung-Haur Yang: Taipei Veterans General Hospital
Chiu-Hua Lin: Institute of Clinical Medicine, National Yang-Ming University
Muh-Hwa Yang: Institute of Clinical Medicine, National Yang-Ming University
Mien-Chie Hung: Graduate Institute of Cancer Biology, College of Medicine, Center for Molecular Medicine, China Medical University and Hospital
Shih-Chieh Hung: Institute of Clinical Medicine, National Yang-Ming University

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: Abstract Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.

Date: 2016
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DOI: 10.1038/ncomms11798

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