α,1,6-Fucosyltransferase (FUT8) regulates cancer-promoting capacities of cancer-associated fibroblasts (CAFs) through the modification of EGFR core fucosylation in non-small cell lung cancer

Abstract BackgroundCancer-associated fibroblasts (CAFs), the main component of the tumor microenvironment (TME) of NSCLC, are activated by phenotypic transformation into myofibroblasts. α,1,6-fucosyltransferase (FUT8), the key enzyme catalyzing core α,1,6-fucosylation (CF), plays important roles in multiple malignancies. In the current study, we investigated the functions and mechanism of CF mediated by FUT8 in CAFs in NSCLC through bioinformatics analysis, retrospective clinical studies and in vitro/in vivo laboratory experiments.MethodsBioinformatics was used to reveal the relationship between FUT8 and CAFs. Resected specimens, clinical data and prognostic information from 135 NSCLC patients were analyzed to assess the prognostic value of FUT8 in CAFs. Primary CAFs and normal lung fibroblasts were extracted from NSCLC patients and cocultured with NSCLC cell lines in a novel noncontact coculture device produced by 3D printing. In vivo, CAF/NSCLC coinjection tumorigenesis assay was performed in nude mice to study the function of FUT8/CF in TME. The mechanisms of FUT8/CF in CAFs regulating the cocultured NSCLC cells were investigated in cell and molecular experiments. ResultsFUT8 in CAFs is an independent risk factor for prognosis. FUT8/CF in CAFs is essential for CAFs to maintain their ability to promote NSCLC. FUT8/CF in CAFs is responsible for the cancer-promoting capacities of CAFs and lead to a malignant tumor microenvironment. CF modification enhances tyrosine phosphorylation of EGFR in CAFs, which causes activation of downstream signalings of EGFR and maintains cancer-promoting properties of CAFs.ConclusionFUT8 regulates cancer-promoting capacities of CAFs via the modification of EGFR CF in non-small cell lung cancer.