Abstract
Tunneling nanotubes (TnTs) are thin channels that temporally connect nearby cells allowing the cell-to-cell trafficking of biomolecules and organelles. The presence or absence of TnTs in human neoplasms and the mechanisms of TnT assembly remains largely unexplored. In this study, we have identified TnTs in tumor cells derived from squamous cell carcinomas (SCC) cultured under bi-dimensional and tri-dimensional conditions and also in human SCC tissues. Our study demonstrates that TnTs are not specific of epithelial or mesenchymal phenotypes and allow the trafficking of endosomal/lysosomal vesicles, mitochondria, and autophagosomes between both types of cells. We have identified focal adhesion kinase (FAK) as a key molecule required for TnT assembly via a mechanism involving the MMP-2 metalloprotease. We have also found that the FAK inhibitor PF-562271, which is currently in clinical development for cancer treatment, impairs TnT formation. Finally, FAK-deficient cells transfer lysosomes/autophagosomes to FAK-proficient cells via TnTs which may represent a novel mechanism to adapt to the stress elicited by impaired FAK signaling. Collectively, our results strongly suggest a link between FAK, MMP-2, and TnT, and unveil new vulnerabilities that can be exploited to efficiently eradicate cancer cells.
Highlights
Cell-to-cell communication is a mechanism for the transit of information essential for coordination of cellular events in multicellular systems
In depth analysis of these structures and the Tunneling nanotubes (TnT) assembled in PC12 cells, which represent the cellular system where TnTs were first identified [14], revealed that the TnTs formed in squamous cell carcinomas (SCC) cells were 1.8-2.3-fold thicker, more durable (1.6-fold), and 2-5-fold larger in length than TnTs of PC12 cells (Supplementary Figure 2)
This work reveals the presence of TnTs in head and neck SCC, describes a new mechanism of direct exchange of cargos between distant SCC cells via TnTs and discloses a not previously identified function for focal adhesion kinase (FAK) and MMP-2 in the formation of these novel cellular structures
Summary
Cell-to-cell communication is a mechanism for the transit of information essential for coordination of cellular events in multicellular systems. TnTs are thin tube structures that connect distant cells forming membrane bridges They have been proved to be a viable mechanism of exchange of biomolecules, pathogens, and organelle between connected cells [5,6,7,8,9,10,11,12]. These intercellular bridges are filled with cytoskeletal filaments, like actin, and may contain microtubules and motor proteins [10, 13,14,15]. Recent reports have demonstrated the existence of TnTs in several cancer cell types [13, 18,19,20]
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