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

机译:通过隧穿纳米管控制鳞状细胞癌中的长距离细胞间通讯和自噬体转移

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摘要

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.
机译:隧道纳米管(TnT)是暂时连接附近细胞的细通道,允许生物分子和细胞器的细胞间运输。人类肿瘤中是否存在TnTs以及TnT组装的机制尚待进一步研究。在这项研究中,我们已经确定了在二维和三维条件下培养的鳞状细胞癌(SCC)和人SCC组织中的肿瘤细胞中的TnTs。我们的研究表明,TnTs不是上皮或间充质表型的特异性,并允许在两种类型的细胞之间转运内体/溶酶体囊泡,线粒体和自噬体。我们已经通过涉及MMP-2金属蛋白酶的机制将粘着斑激酶(FAK)确定为TnT组装所需的关键分子。我们还发现,目前正在临床开发中的用于癌症治疗的FAK抑制剂PF-562271会损害TnT的形成。最后,FAK缺陷细胞通过TnTs将溶酶体/自噬体转移到FAK熟练细胞中,这可能是适应FAK信号转导所引起的应激的新机制。总的来说,我们的研究结果强烈暗示了FAK,MMP-2和TnT之间的联系,并揭示了可用于有效根除癌细胞的新漏洞。

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