Chen W.-J.CHAO-CHI HOYIH-LEONG CHANGChen H.-Y.Lin C.-A.THAI-YEN LINGSUNG-LIANG YUYuan S.-S.Louisa Chen Y.-J.Lin C.-Y.SZU-HUA PANHAN-YI E. CHOUChang G.-C.Chu W.-C.Lee Y.-M.Lee J.-Y.Lee P.-J.Li K.-C.HUEI-WEN CHENPAN-CHYR YANG2022-03-092022-03-0920142041-1723https://www.scopus.com/inward/record.uri?eid=2-s2.0-84897058262&doi=10.1038%2fncomms4472&partnerID=40&md5=a754bb29d6440b4cc567367b78703dd4https://scholars.lib.ntu.edu.tw/handle/123456789/596847Cancer 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. ? 2014 Macmillan Publishers Limited. All rights reserved.[SDGs]SDG3octamer transcription factor 4; organic cation transporter 3; somatomedin B; somatomedin receptor; transcription factor NANOG; homeodomain protein; IGF1R protein, human; NANOG protein, human; octamer transcription factor 4; POU5F1 protein, human; somatomedin B; somatomedin receptor; Thy 1 antigen; cancer; plasticity; signaling; survival; tumor; article; cancer cell culture; cancer growth; cancer patient; cancer staging; cancer stem cell; cancer survival; cell differentiation; fibroblast; human; human cell; lung non small cell cancer; major clinical study; paracrine signaling; primary cell culture; protein expression; recurrence free survival; signal transduction; transcriptomics; tumor microenvironment; adenocarcinoma; aged; animal; cancer stem cell; cancer transplantation; cell culture; female; fibroblast; gene expression profiling; genetics; lung tumor; male; metabolism; middle aged; mouse; small cell lung cancer; squamous cell carcinoma; very elderly; Adenocarcinoma; Aged; Aged, 80 and over; Animals; Antigens, Thy-1; Carcinoma, Squamous Cell; Cells, Cultured; Female; Fibroblasts; Gene Expression Profiling; Homeodomain Proteins; Humans; Insulin-Like Growth Factor II; Lung Neoplasms; Male; Mice; Middle Aged; Neoplasm Transplantation; Neoplastic Stem Cells; Octamer Transcription Factor-3; Paracrine Communication; Receptors, Somatomedin; Small Cell Lung Carcinoma; Tumor Microenvironmentjournal article10.1038/ncomms44722-s2.0-84897058262