alpha 1,6-Fucosyltransferase (FUT8) regulates the cancer-promoting capacity of cancer-associated fibroblasts (CAFs) by modifying EGFR core fucosylation (CF) in non-small cell lung cancer (NSCLC)

Cancer-associated fibroblasts (CAFs) are the main cancer-promoting component in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). alpha 1,6-Fucosyltransferase (FUT8), the key enzyme catalyzing core alpha 1,6-fucosylation (CF), plays a promoting role in multiple malignancies. In the current study, we investigated the function of FUT8 in CAFs and elucidated the mechanism through which FUT8 regulates the cancer-promoting capacity of CAFs in NSCLC. A bioinformatics analysis was performed to reveal the relationship between FUT8 and CAFs. Resected specimens from NSCLC patients were analyzed to assess the expression of FUT8 in CAFs. Primary CAFs and normal lung fibroblasts (NLFs) were extracted from NSCLC patient specimens and were co-cultured with NSCLC cell lines in a novel 3D-printed non-contact co-culture device. An In vivo CAF/NSCLC co-injection tumorigenesis assay was performed using nude mice to study the function of FUT8/CF in TME formation. The current study revealed that FUT8-mediated CF in CAFs plays a positive role in the cancer-promoting capacity of these cells. FUT8 overexpression was observed in CAFs isolated from some lung adenocarcinoma cases. Further investigation showed that FUT8/CF in CAFs promoted the formation of an invasive and malignant TME in vivo and in vitro, and the resulting NSCLC cells exhibited faster proliferation and increased invasiveness. EGFR signaling exerts a catalytic effect on the cancer-promoting capacity of CAFs and is regulated by the CF modification of the EGFR protein.