Abstract 4516: Suppression of metastasis by inhibiting nanoscale physical communication of cancer cell and the endothelium

Abstract

The progression of metastasis proceeds through the physical communication of cancer cells with the endothelium via tunneling nanotubes (TNTs). Restriction on the cancer cell and the endothelium communication by inhibiting TNT formation can lead to breakthrough advancement in the treatment of metastasis. However, the mechanistic interpretation about the formation of TNTs between the cancer cells and the endothelium has been poorly defined in literature. Our study integrates the investigation of mechanism behind the TNT formation and introduction of a pharmacological inhibitor for TNT formation. The nanobridges are primarily composed of cytoskeletal elements such as actin and tubulin, which originates from the energy dependent remodeling of membrane cytoskeletal elements. Here, we propose that the members of Rho-family of GTPases, Cdc42, Ral and Rac along with exocyst complex, are involved in the actin polymerization based on their localization to the nanobridges between the metastatic cancer cells and the endothelium. A significant decrease in mitochondrial transfer and TNT formation has been observed when the inhibitor for Cdc42/Rac1 GTPase inhibitor (ML141), and a geranylgeranyltransferase 1 inhibitor (L-778,123) has been employed in the co-culture. The amount of mitochondrial transfer was evaluated with flow cytometry and the number of TNT formation was counted from imaging, which in case of inhibitors was highly reduced. Simultaneously the involvement of exocyst complex was confirmed through imaging. The proteins involved in the exocyst complex co-localize with the nanotubes and was further validated by siRNA-based knock down study. The nanotubular pathways are the primary mode of communication between cancer cell and endothelium, which leads to the conversion of healthy endothelium to a pathological one. Hindering the TNT mediated communication via pharmacological inhibitors can reduce the chance of metastasis. Conclusion: Investigation of molecular mechanism behind the TNT formation and employing innovative ways to have restriction over that can be a potential next generation therapeutic module for controlling metastasis. Reference: Connor Y, Tekleab S, Nandakumar S, Walls C, Tekleab Y, Reiberger T, Husain A, Gadish O, Sabbisetti V, Kaushik S, Sehrawat S, Kulkarni A, Dvorak H, Zetter B, Jain RK, Edelman E, Sengupta S. Physical nanoscale conduits-mediated communication between tumor cells and endothelium enables a metastatic hijack. Nature Communications (2015) 6:8671. Citation Format: Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Shiladitya Sengupta. Suppression of metastasis by inhibiting nanoscale physical communication of cancer cell and the endothelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4516.