ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Simple Summary Despite the numerous novel pharmacological and immunological approaches for multimodal glioma treatments that have been proposed in recent years, glioma phenotypic and genotypic spatial profiles in the course of treatments remain heterogeneous and, therefore, represent the biggest challenge for patient outcome. The elimination of glioma heterogeneity is an established chemotherapeutic goal. The role of the mRNA-binding protein of ELAV-family HuR in homotypic and heterotypic cell fusions via permanent intercellular membrane fusions and temporal intercellular tunneling nanotube formations in the glioma microenvironment leading to glioma heterogeneity will be discussed in our review with implications of HuR inhibitors in the prevention of these processes. Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.