Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling

Wan-Jiun Chen, Chao-Chi Ho, Yih-Leong Chang, Hsuan-Yu Chen, Chih-An Lin, Thai-Yen Ling, Sung-Liang Yu, Shin-Sheng Yuan, Yu-Ju Louisa Chen, Chien-Yu Lin, Szu-Hua Pan, Han-Yi Elizabeth Chou, Yu-Ju Chen, Gee-Chen Chang, Wen-Cheng Chu, Yee-Ming Lee, Jen-Yi Lee, Pei-Jung Lee, Ker-Chau Li, Huei-Wen Chen () and Pan-Chyr Yang ()
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Wan-Jiun Chen: Graduate Institute of Oncology, National Taiwan University Medical College
Chao-Chi Ho: National Taiwan University Hospital and National Taiwan University Medical College
Yih-Leong Chang: National Taiwan University Medical College
Hsuan-Yu Chen: Institute of Statistical Science, Academia Sinica
Chih-An Lin: National Taiwan University Medical College
Thai-Yen Ling: National Taiwan University Medical College
Sung-Liang Yu: National Taiwan University Medical College
Shin-Sheng Yuan: Institute of Statistical Science, Academia Sinica
Yu-Ju Louisa Chen: Institute of Statistical Science, Academia Sinica
Chien-Yu Lin: Institute of Statistical Science, Academia Sinica
Szu-Hua Pan: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College
Han-Yi Elizabeth Chou: Graduate Institute of Oral Biology, National Taiwan University Dentistry College
Yu-Ju Chen: Graduate Institute of Chemistry, Academia Sinica
Gee-Chen Chang: Faculty of Medicine, School of Medicine, National Yang-Ming University
Wen-Cheng Chu: Graduate Institute of Toxicology, National Taiwan University Medical College
Yee-Ming Lee: Graduate Institute of Toxicology, National Taiwan University Medical College
Jen-Yi Lee: Graduate Institute of Toxicology, National Taiwan University Medical College
Pei-Jung Lee: Graduate Institute of Toxicology, National Taiwan University Medical College
Ker-Chau Li: Institute of Statistical Science, Academia Sinica
Huei-Wen Chen: Graduate Institute of Toxicology, National Taiwan University Medical College
Pan-Chyr Yang: Graduate Institute of Oncology, National Taiwan University Medical College

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4472

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