The Clinical Significance of Fucosyltransferase 8 (Fut8) Expression and Its Impact on Tumor Physiology in Glioma

Gliomas are solid tumors that originate from glial cells in the brain or spine. Gliomas account for 80.7% of malignant brain tumor and high-grade gliomas, especially grade IV glioma (glioblastoma [GBM]), are intractable due to lack of therapeutic drugs and recurrence; despite intensive medical treatment, patients with GBM have a low 5-year survival rate of 5.5%. In this study, we will try to improve currently used therapies by identification of a prognostic factor and therapeutic target, fucosyltransferase 8 (FUT8), for glioma treatment. FUT8 belongs to the fucosyltransferase family and is responsible for catalyzing the synthesis of core-fucose, which is the attachment of a fucose residue in α1,6 linkage to the first GlcNAc of N-glycan. Although the impact of FUT8 on cell invasion, tumor metastasis, and immunomodulation has been described in many cancers, it has not been described in glioma. We will first correlate tumor FUT8 expression with clinicopathological factors and overall survival of glioma patients to identify the role and evaluate the potential of FUT8 as a prognostic factor in glioma. Clinical data and FUT8 RNA expression in specimens from at least 150 newly diagnosed glioma patients will be collected and analyzed. On other hand, the association of FUT8 expression with tumor recurrence and treatment resistance will also be analyzed. For examination of the FUT8-mediated molecular mechanism, we will first try to establish glioma primary neurosphere cell lines for in vitro cell culture experiments and to perform the in vivo intracranial patient-derived xenograft (PDX) mouse models. The impact of FUT8 expression on glioma tumor cell phenotypes and the identification of the target molecules and underlying signaling pathways that regulate FUT8-mediated phenotype changes will be done. Glioma commercial and primary neurosphere cells will be modified to enhance or suppress FUT8 expression, and then phenotype assays, such as cell proliferation and cell invasion, will be performed to evaluate the effect of FUT8 expression on cell phenotypes. Changes of receptor glycosylation and activation as well as its downstream signaling pathway will be analyzed. Rescue assays and in vivo mouse xenograft models will also be performed to validate the correlation among FUT8 expression, the receptor activation, and the phenotype change. Finally, we will evaluate the potential of FUT8 inhibitors as therapeutic drugs in treating glioma by applying FUT8 inhibitors to culture cells or PDX models. This study will improve our understanding to the impact of fucosylation on regulating glioma progression and the knowledge of glycosylation in cancer biology, and further bring up the possibility of FUT8 as a future therapeutic target in treating GBM.

Project ID:PC10901-2022
External Project ID:MOST108-2314-B182A-158-MY2