Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Silvana Valdebenito,Ross Luu,Shaily Malik,Eliseo A Eugenin,Brendan Prideaux,Megan Mitchell,Krishna Bhat,George Okafo,Olivier Loudig

doi:10.1038/s41598-021-93775-8

Abstract

Cell-to-cell communication is essential for the development and proper function of multicellular systems. We and others demonstrated that tunneling nanotubes (TNT) proliferate in several pathological conditions such as HIV, cancer, and neurodegenerative diseases. However, the nature, function, and contribution of TNT to cancer pathogenesis are poorly understood. Our analyses demonstrate that TNT structures are induced between glioblastoma (GBM) cells and surrounding non-tumor astrocytes to transfer tumor-derived mitochondria. The mitochondrial transfer mediated by TNT resulted in the adaptation of non-tumor astrocytes to tumor-like metabolism and hypoxia conditions. In conclusion, TNT are an efficient cell-to-cell communication system used by cancer cells to adapt the microenvironment to the invasive nature of the tumor.

Highlights

Cell-to-cell communication is essential for the development and proper function of multicellular systems
A co‐culture system to mimic the interface tumor‐healthy tissue demonstrates that tunneling nanotubes (TNT) for‐ mation is induced by oxidative stress
The present study demonstrates first that (1) TNT mediate a long-range directed communication between GBMGBM and GBM-primary astrocytes; (2) TNT are induced by oxidative stress; (3) TNT enable the transfer of enlarged mitochondria from cancer cells into neighboring primary astrocytes; (4) mitochondria from cancer cells are enlarged and have an altered metabolism that favors cancer development and tumor metabolism adaptation to the environment; (5) TNT generated in tumor cells protect surrounding non-tumor cells from hypoxia-induced apoptosis, probably to maintain tumor survival

Summary

Introduction

Cell-to-cell communication is essential for the development and proper function of multicellular systems. Our analyses demonstrate that TNT structures are induced between glioblastoma (GBM) cells and surrounding non-tumor astrocytes to transfer tumor-derived mitochondria. Our data demonstrated that TNT formation enables the spread of O(6)-Methylguanine-DNA methyltransferase (MGMT) between resistant and sensitive cells to TMZ and radiation treatment within the tumor to protect the tumor from treatment[23]. The association of mitochondrial dysfunction and carcinogenesis is well e stablished[35,36,37,38,39], but whether TNT formation and associated mitochondrial transfer participate in tumor adaptation to the microenvironment is unknown. We propose that TNT structures contribute to the exchange of tumor-derived mitochondria into neighboring healthy cells resulting in their adaptation to the new tumor-related metabolism and hypoxic conditions

Methods

Results

Conclusion