The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance

Abstract

Intercellular communications play a major role in tissue homeostasis. In pathologies such as cancer, cellular interactions within the tumor microenvironment (TME) contribute to tumor progression and resistance to therapy. Tunneling nanotubes (TNTs) are newly discovered long-range intercellular connections that allow the exchange between cells of various cargos, ranging from ions to whole organelles such as mitochondria. TNT-transferred mitochondria were shown to change the metabolism and functional properties of recipient cells as reported for both normal and cancer cells. Metabolic plasticity is now considered a hallmark of cancer as it notably plays a pivotal role in drug resistance. The acquisition of cancer drug resistance was also associated to TNT-mediated mitochondria transfer, a finding that relates to the role of mitochondria as a hub for many metabolic pathways. In this review, we first give a brief overview of the various mechanisms of drug resistance and of the cellular communication means at play in the TME, with a special focus on the recently discovered TNTs. We further describe recent studies highlighting the role of the TNT-transferred mitochondria in acquired cancer cell drug resistance. We also present how changes in metabolic pathways, including glycolysis, pentose phosphate and lipid metabolism, are linked to cancer cell resistance to therapy. Finally, we provide examples of novel therapeutic strategies targeting mitochondria and cell metabolism as a way to circumvent cancer cell drug resistance.

Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

“…Independent of HIV-1 infection, we also noticed that cmMTB-treated cells depleted for Siglec-1 displayed a decreasing tendency to transfer mitochondria among them. As TNT-transferred mitochondria are known to alter the metabolism and functional properties of recipient cells under steady state conditions or in the cancer context, it implies that Siglec-1 may also influence key important metabolic pathways such as glycolysis, pentose phosphate and lipid metabolism, among others (Hekmatshoar et al, 2018). This is important because, for example, the gain of cancer drug resistance is directly associated to TNT-mediated mitochondria transfer, thus Siglec-1 may represent a novel therapeutic strategy to overcome cancer cell drug resistance.…”

Investigating Tunneling Nanotubes in Cancer Cells: Guidelines for Structural and Functional Studies through Cell Imaging

“…In contrast, the contribution of tubulin in the mechanisms of TNT formation may be cell type specific since blockage of tubulin did not affect the TNT formation in HBEC-3 cells [11] while stressed PC12 cells form tubulin-dependent TNTs [10]. In cancer cells, the role of TNT microtubules is generally, but not exclusively, associated with the transfer of mitochondria, endoplasmic reticulum, and lysosome vesicles (Figure 8) [2,17,25,35]. While the transport is demonstrated within TNT1 that present a clear cytosolic channel, the existence of cargo-TNT2 is less obvious [20].…”

“…On the other hand, TNTs convey resistance to chemotherapy by exporting the mitochondria [15,16]. This transfer of mitochondria allows tumor cells to develop one of the hallmarks of tumors, i.e., a metabolic plasticity, in order to acquire migration, proliferation, and resistance properties, particularly to cisplatin and paclitaxel [6,17].…”

Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

“…However, during the past 15 years TNT-like structures have been observed in various cell lines in culture, in primary cells and in tissues, and were shown to allow the transfer of different cargoes, ranging from ions to organelles [reviewed in 3,[4][5][6][7]. Based on the observations of the transfer of various cargoes, several functions of TNTs have been proposed.…”