Abstract LB-025: Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism

Abstract

Abstract Cell-cell communication plays important roles in promoting tumor growth and metastasis, and these events are frequently targeted by therapies. The generation of extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are beginning to be appreciated as one such form of communication that has important consequences in cancer. MVs are small vesicular structures (0.1-2 μm) that are derived from plasma membranes and are shed into the cell's surroundings; exosomes (30-100 nm) are rerouted endosomes that are released by the fusion of multi-vesicular bodies with the plasma membrane. Both types of EVs influence the behavior of recipient cells through the transfer of their cargo, which includes oncogenic factors, signaling proteins, RNA transcripts, and cytoskeletal components. However, the mechanism through which cargo is selectively trafficked to EVs has not yet been elucidated. We have discovered that disrupting microtubule dynamics in the MDAMB231 breast cancer cell line using the microtubule inhibitor nocodazole has the intriguing effect of significantly increasing the amount of the anti-apoptotic factor survivin that is contained within the EVs shed by these cells. This finding has been replicated in several additional human cancer cell lines and also when using the chemotherapy agent Paclitaxel (Taxol), which also inhibits microtubule dynamics. When MVs were separated from exosomes using procedures that were developed to resolve these two classes of EVs from MDAMB231 cell conditioned medium, survivin was found to be a specific cargo of exosomes and was absent from MVs. Moreover, the exosomes containing survivin enhanced the survival of recipient cells exposed to serum-starvation. Overall, these results show how a specific protein (e.g. survivin) can be selectively packaged into exosomes, as well as shed light on a novel mechanism that underlies Paclitaxel resistance. Citation Format: Bridget T. Kreger, Marc Antonyak, Richard Cerione. Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-025. doi:10.1158/1538-7445.AM2015-LB-025