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

Abstract

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 β-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.

Scaled preparation of extracellular vesicles from conditioned media

“…Altogether, the data challenge the accuracy of particle numbers for the evaluation of sEV preparation techniques. In addition to IFCM other 2nd generation EV analysis devices have been developed, such as the plasmon resonance device NanoView [57], the NanoFCM, a flow cytometer designed for sub-micron particles [58] the ZetaView Quatt, an NTA optimized for the tracking of fluorescently labelled particles [59], and the direct stochastic optical reconstruction (dSTORM) device, the Nanoimager [60]. These and other 2nd generation analysis devices are currently used by an increasing number of different research groups.…”

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

“…Cancer cells derived exosomes contribute to chemo-resistance in multiple cancers, including BC ( 6 , 7 ), and we next investigated whether PR-BC-exo affected paclitaxel-resistance in PS-BC cells. To explore this issue, the exosomes secreted by PR-BC cells with or without gp96-deficiency were incubated with PS-BC cells, and our data showed that PKH67-labelled exosomes translocated into the PS-BC cells ( Figure 3A ).…”

“…Thus, it becomes necessary and meaningful to delve into the molecular mechanisms by which BC cells transform from paclitaxel-sensitive BC (PS-BC) cells into the paclitaxel-resistant BC (PR-BC) cells. In recent studies, it draws our attention that cancer cells derived exosomes play critical role in regulating paclitaxel-resistance in BC ( 6 , 7 ). Specifically, data from Pederson et al.…”

“…Specifically, data from Pederson et al. show that paclitaxel treatment is able to alter the secretion patterns of extracellular vesicles in BC cells ( 6 ), and Yang et al. further evidence that chemotherapy-elicited microRNAs (miRNAs)-containing exosomes promote BC cell stemness and chemoresistance ( 7 ).…”

IL‐8 correlates with nonresponse to neoadjuvant nivolumab in HPV positive HNSCC via a potential extracellular vesicle miR‐146a mediated mechanism

“…sEV are secreted by virtually all cell types and released into the circulation, thus making them accessible via liquid biopsy. It is well‐established that cancer cells can alter their sEV cargo in response to treatment, allowing them to alter the TME to maintain favorable conditions for continued growth 15–17 . For this reason, sEV offer a wealth of information as to the state of their cells of origin, possibly allowing for personalized treatment options to improve patient outcomes.…”