title: Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling.
abstract: Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable primary culture of Oct3/4(+)/Nanog(+) lung CSCs fed with CD90(+) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.
authors.affiliation: 1] Graduate Institute of Oncology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan [3] Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Wan-Jiun
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Chao-Chi
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Department of Pathology and Graduate Institute of Pathology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Chih-An
authors.initials: CA
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Thai-Yen
authors.initials: TY
authors.lastname: Ling
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Shin-Sheng
authors.initials: SS
authors.lastname: Yuan
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yu-Ju Louisa
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.affiliation: Graduate Institute of Oral Biology, National Taiwan University Dentistry College, Taipei 10051, Taiwan.
authors.forename: Han-Yi Elizabeth
authors.initials: HY
authors.lastname: Chou
authors.affiliation: Graduate Institute of Chemistry, Academia Sinica, Taipei 10051, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: 1] Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan [2] Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chu
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Jen-Yi
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: 1] Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan [2] Department of Statistics, University of California, Los Angeles, California 90095, USA.
authors.forename: Ker-Chau
authors.initials: KC
authors.lastname: Li
authors.affiliation: 1] Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Huei-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: 1] Graduate Institute of Oncology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 10051, Taiwan [3] Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism; D018800:Thy-1 Antigens / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D018398:Homeodomain Proteins; C000597236:IGF1R protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D017451:Receptors, Somatomedin; D018800:Thy-1 Antigens; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1