Glioblastoma (GB) is one of the most aggressive and treatment-resistant forms of cancer. 5-year overall survival of GB patients remains at or below 5% and has not improved significantly in the past few decades despite advances in chemotherapeutic treatment and molecular diagnostics. Despite standard-of-care treatment encompassing maximal safe resection, adjuvant chemoradiation and chemotherapy with the alkylating agent temozolomide, GB is nearly certain to recur. Improved understanding of the underlying molecular and cellular biology will be crucial to designing more rational strategies for effective treatment.

Intercellular communication, a process that is critical to cancer cell development, invasion, and metabolism, has been identified as a potential mechanism of adaptation and stress response in GB. Discovery and characterization of long cytoplasmic bridge-like extensions connecting distant cells called tunneling nanotubes (TNTs) and tumor microtubes (TMs) (cytoplasmic projections connecting cancer cells in vitro and in vivo) have produced new evidence that these cellular protrusions promote invasive capacity and development of resistance to treatment in GB. The study of TNTs and TMs (referred to herewith as tumor membrane tubes, or TTs) is a rapidly growing field of cell biology, with strong potential to explain how the effects of vital cellular cargo, including organelles such as mitochondria, lysosomes, and others that play a role in cancer metabolism, can be amplified in vivo. Confocal imaging has detected TTs in human tumors following surgical resection, supporting theirs in vivo relevance in many invasive forms of cancer. Examination of intercellular communication occurring via TTs in an in vivo orthotopic animal model of GB has opened a new avenue for investigation of intercellular transfer of organelles in cancer in general, and especially in this form of cancer.

We have determined that TNTs are universally upregulated in tumor cells when subjected to physiologic or metabolic stressors, a consistent phenomenon in vitro and in vivo across many cancer types. Our collective preliminary and published data strongly support bi-directional intercellular exchange of mitochondria and lysosomes between cancer cells, including TNT-mediated mitochondrial transport between GB cells in vivo, and also between GB cells and normal astrocytes or mesenchymal cells. Downstream effects of this exchange include increased motility and invasive capacity of recipient cells. We hypothesize that TNT plays a key role in the susceptibility to GB and chemo/radioresistance. TNTs are a novel system that GB cells exploit by harnessing intercellular communication to thrive and survive in response to physiologic and metabolic stress. We propose the following three Aims to investigate the role of TTs in inter-organelle communication in cancer: Thus, targeting TNT could be a new mechanism to target GB and to cure this disease.