FGFR4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer.
Tumor cells evolve by interacting with the local microenvironment; however, the tumor-stroma interactions that govern tumor metastasis are poorly understood. In this study, proteomic analyses reveal that coculture with tumor-associated fibroblasts (TAF) induces significant overexpression of FGFR4, but not other FGFRs, in colorectal cancer cell lines. Mechanistic study shows that FGFR4 plays crucial roles in TAF-induced epithelial-to-mesenchymal transition (EMT) in colorectal cancer cell lines. Accumulated FGFR4 in cell membrane phosphorylates β-catenin, leading to translocation of β-catenin into the nucleus. Further, TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. Our study shows a pivotal role of FGFR4 in tumor-stroma interactions during colorectal cancer metastasis, and suggests novel therapeutic opportunities for the treatment of colorectal cancer.
Authors' Affiliations: The State Key Laboratory of Biotherapy and Cancer Center, and Department of Hepatobiliary Pancreatic Surgery, West China Hospital, Sichuan University; The School of Biomedical Sciences, Chengdu Medical College; Department of Oncology, Sichuan Provincial People's Hospital, Chengdu, People's Republic of China; Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota; and Monash University, Department of Biochemistry and Molecular Biology, Clayton, Victoria, Australia.
Rui
R
Liu
Jingyi
J
Li
Ke
K
Xie
Tao
T
Zhang
Yunlong
Y
Lei
Yi
Y
Chen
Lu
L
Zhang
Kai
K
Huang
Kui
K
Wang
Hong
H
Wu
Min
M
Wu
Edouard C
EC
Nice
Canhua
C
Huang
Yuquan
Y
Wei
D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D050784:Proto-Oncogene Protein c-ets-1; D051176:beta Catenin; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4