The microdissected gene expression landscape of nasopharyngeal cancer reveals vulnerabilities in FGF and noncanonical NF-κB signaling

Abstract

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)–positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.

Canonical fibroblast growth factors in viral infection

“…84 Also, reduced expression of Sprouty1 in nasopharyngeal tumours showed that EBV-mediated transformation was associated to FGF signalling. 85…”

“…Nasopharingeal epithelium transformation, associated to EBV infection, was shown to be promoted by viral protein LMP1‐activated FGFR1 84 . Also, reduced expression of Sprouty1 in nasopharyngeal tumours showed that EBV‐mediated transformation was associated to FGF signalling 85 …”

EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis

“…The activity of NF-kB signals has been reported to contribute to metabolic alteration (Mauro et al, 2011;Johnson and Perkins, 2012). In NPC, aberrant activation of NF-kB pathway, which may result from the inactivating mutations of NF-kBnegative regulators such as NFKBIA, CYLD, and TNFAIP3 (Zheng et al, 2016;Li et al, 2017), was universally observed and it is believed to be closely related to the infection of EBV (Lo et al, 2006;de Oliveira et al, 2010;Tay et al, 2022). Consistently, EBV infection was showed to downregulate the expression levels of CYLD in NPC cells (Li et al, 2021), and CYLD deficiency could increase the transcriptional activity of PFKFB3, which is a key regulator of glycolysis, to enhance glycolysis (Wang et al, 2022).…”

Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment

“…Aberrantly activated FGF signaling is involved in the accumulation of tumor-infiltrating MDSCs and M2-TAMs [ 23 ], remodeling the metabolism of NPC cells and promoting metastasis. Therefore, FGF2/FGFR2 may be a crucial target in NPC [ 24 ]. FGF/FGFR inhibitors promote further activation and infiltration of effector T cells into the TME by normalizing tumor vasculature.…”