title: Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas.
abstract: Cancer stem-like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment.
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Sun
authors.affiliation: Innovation Center for Cell Biology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Sheng Zhong
authors.initials: SZ
authors.lastname: Duan
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Henghua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Chaoji
authors.initials: C
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai, P.R. China. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. zhzhy.onco@gmail.com zhzhy.onco@hotmail.com.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage; D061251:Primary Cell Culture; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles; D011725:Pyridines / Q000008:administration & dosage; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C529739:Fzd8 protein, human; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D011956:Receptors, Cell Surface; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met