Eribulin and Paclitaxel Differentially Alter Extracellular Vesicles and Their Cargo from Triple-Negative Breast Cancer Cells

Simple Summary Cancer cells release small vesicles called extracellular vesicles (EVs) and these vesicles and their cargo promote cancer progression. The release of these vesicles is coordinated by cellular structures called microtubules. Drugs used in the treatment of breast cancer include eribulin and paclitaxel and they function by inhibiting microtubules. We investigated if these drugs would alter the release of vesicles from breast cancer cells and change their cargo. While our results show that these drugs do not alter the concentration of vesicles released, eribulin but not paclitaxel reduced levels of an important cargo called ILK. This is significant because ILK promotes cancer progression in breast cancer models. These results show that drugs can differently affect the release and cargo of extracellular vesicles and this could be significant for their clinical actions. Extracellular vesicles play a central role in intercellular communication and contribute to cancer progression, including the epithelial-to-mesenchymal transition (EMT). Microtubule targeting agents (MTAs) including eribulin and paclitaxel continue to provide significant value in cancer therapy and their abilities to inhibit oncogenic signaling pathways, including eribulin's capacity to reverse EMT are being revealed. Because microtubules are involved in the intracellular trafficking required for the formation and cargo loading of small extracellular vesicles (sEVs), we investigated whether MTA-mediated disruption of microtubule-dependent transport would impact sEV release and their cargo. Eribulin and paclitaxel caused an intracellular accumulation of CD63, a tetraspanin component of sEVs, in late/multivesicular endosomes of triple-negative breast cancer cells, consistent with the disruption of endosomal sorting and exosome cargo loading in these cells. While the concentrations of sEVs released from MTA-treated cells were not significantly altered, levels of CD63 and the CD63-associated cargos, ILK and beta-integrin, were reduced in sEVs isolated from eribulin-treated HCC1937 cells as compared to vehicle or paclitaxel-treated cells. These results show that eribulin can reduce specific sEV cargos, including ILK, a major transducer of EMT in the tumor microenvironment, which may contribute to eribulin's ability to reverse EMT to promote anticancer efficacy.

Automated summary

The study investigated the impact of microtubule-targeting drugs eribulin and paclitaxel on the release and cargo of extracellular vesicles from breast cancer cells. While both drugs did not alter the concentration of vesicles released, eribulin reduced the levels of ILK, a key cargo promoting cancer progression. This differential effect highlights the potential clinical significance of drug-induced changes in extracellular vesicles and their cargo. Overall, the findings suggest that eribulin can specifically reduce certain cargo in extracellular vesicles, potentially contributing to its efficacy in reversing epithelial-to-mesenchymal transition in breast cancer.