Epstein–Barr Virus Induces Adipocyte Dedifferentiation to Modulate the Tumor Microenvironment

Abstract

The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins. In infected adipocytes, lipolysis was stimulated through enhanced expression of lipases and the AMPK metabolic pathway. The EBV-mediated imbalance in energy homeostasis was further confirmed by increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines. Clinically, enhanced serum levels of free fatty acids in patients with NPC correlated with poorer recurrence-free survival. EBV-induced delipidation stimulated dedifferentiation of adipocytes into fibroblast-like cells expressing higher levels of S100A4, a marker protein of cancer-associated fibroblasts (CAF). IHC analyses of bone marrow metastatic NPC and salivary LELC revealed similar structural changes of dedifferentiated adipocytes located at the boundaries of EBV+ tumors. S100A4 expression in adipose tissues near tumor beds correlated with fibrotic response, implying that CAFs in the tumor microenvironment are partially derived from EBV-induced dedifferentiated adipocytes. Our data suggest that adipose tissue serves as an EBV reservoir, where EBV orchestrates the interactions between adipose tissues and tumor cells by rearranging metabolic pathways to benefit virus persistence and to promote a protumorigenic microenvironment. Significance: This study suggests that Epstein–Barr virus hijacks adipocyte lipid metabolism to create a tumor-promoting microenvironment from which reactivation and relapse of infection could potentially occur.

Integration Profiling Between Plasma Lipidomics, Epstein–Barr Virus and Clinical Phenomes in Nasopharyngeal Carcinoma Patients

“…The titers of serum EBV antibodies are known to increase dramatically in NPC patients ( Chen et al, 2015 ). Interestingly, EBV has also been shown to be able to infect primary human adipocytes in vitro , leading to increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines ( Liu et al, 2021 ). Further, EBV-encoded latent membrane protein 1 and EBV-encoded RNAs were shown to promote cell proliferation by upregulating fatty acid synthase in NPC cells ( Lo et al, 2018 ) whereas EBV-encoded latent membrane protein 2A (LMP2A) were shown to promote lipid accumulation by blocking adipose triglyceride lipase in NPC cells, resulting in an enhanced cell migration ( Zheng et al, 2020 ).…”

“…Although they do not seem to affect the migration or invasion of cancer cells, EBV-encoded RNAs might confer a low-density lipoprotein-dependent proliferation in NPC cells ( Daker et al, 2013 ). Furthermore, EBV could target adipocytes to build a cancer-promoting environment by rewiring lipid metabolism, leading to increased levels of free fatty acids, glycerol, and proinflammatory cytokines ( Liu et al, 2021 ). Indeed, increased serum levels of free fatty acids have been shown to indicate a poor prognosis in NPC patients ( Liu et al, 2021 ).…”

“…Furthermore, EBV could target adipocytes to build a cancer-promoting environment by rewiring lipid metabolism, leading to increased levels of free fatty acids, glycerol, and proinflammatory cytokines ( Liu et al, 2021 ). Indeed, increased serum levels of free fatty acids have been shown to indicate a poor prognosis in NPC patients ( Liu et al, 2021 ).…”

SARS-CoV-2 infection as a potential risk factor for the development of cancer

“…Resistance to oncolytic virus therapy has also been shown to be a lipid-dependent phenomenon ( Surendran et al, 2023 ). It has been suggested that EBV infection modulates gene expression in adipocytes, leading to dysregulation of their functionality and consequent changes in the tumour microenvironment ( Liu et al, 2021 ).…”

Beyond Viral Infections: The Multifaceted Roles of Human Papillomavirus and Epstein-Barr Virus in Shaping the Tumor Microenvironment

“…In oncology, delving deeper into the nuanced and complex mechanisms orchestrated by viruses such as HPV and EBV within the TME is critical in fostering the evolution of potent therapeutic strategies. These viruses function as powerful catalysts, instigating a myriad of alterations within the TME, thereby influencing the pathogenesis and progression of associated malignancies [20,21]. Thus, it is paramount to unravel the intricate interplay between these viral entities and the TME to facilitate the development of targeted and effective therapies.…”