Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells.
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.
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Chen-Chi
CC
Liu
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Shih-Pei
SP
Lin
Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Han-Shui
HS
Hsu
Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.|Department of Surgery, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Shung-Haur
SH
Yang
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Chiu-Hua
CH
Lin
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Muh-Hwa
MH
Yang
Graduate Institute of Cancer Biology, College of Medicine, Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan.|Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mien-Chie
MC
Hung
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Medical Research and Education, Stem Cell Laboratory, Taipei Veterans General Hospital, Taipei 112, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.|Department of Orthopedics, Integrative Stem Cell Center, China Medical University Hospital, Taichung 404, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
Shih-Chieh
SC
Hung
D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008207:Lymphatic Metastasis; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D024041:Non-Fibrillar Collagens / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D000097794:Kalinin; D000097805:Collagen Type XVII
D001324:Autoantigens; D015815:Cell Adhesion Molecules; D008156:Luciferases; D024041:Non-Fibrillar Collagens; D054648:Protein Phosphatase 2; D050796:STAT3 Transcription Factor; D000097794:Kalinin; D000097805:Collagen Type XVII; C494086:STAT3 protein, human