Control of long-distance cell-to-cell communication and autophagosome transfer in squamous cell carcinoma via tunneling nanotubes

// Ines Saenz-de-Santa-Maria 1 , Cristobal Bernardo-Castineira 1 , Eduardo Enciso 2 , Inmaculada Garcia-Moreno 3 , Jose Luis Chiara 4 , Carlos Suarez 1 , Maria-Dolores Chiara 1 1 Servicio de Otorrinolaringologia, Hospital Universitario Central de Asturias, Instituto Universitario de Oncologia del Principado de Asturias, CIBERONC, Universidad de Oviedo, Oviedo, Spain 2 Facultad de Ciencias Quimicas, Universidad Complutense de Madrid, Madrid, Spain 3 Instituto Quimica-Fisica “Rocasolano”, IQFR-CSIC, Madrid, Spain 4 Instituto de Quimica Organica General, IQOG-CSIC, Madrid, Spain Correspondence to: Maria-Dolores Chiara, email: mdchiara.uo@uniovi.es Keywords: tunneling nanotubes, cell communication, FAK, MMP-2, squamous cell carcinomas Received: July 04, 2016      Accepted: February 06, 2017      Published: February 18, 2017 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.