Background: Drug resistance results in treatment failure in over 90% of patients with metastatic disease.  A unique type of resistance is multi-drug resistance (MDR), whereby cells become cross resistant to many chemotherapeutics. Ubiquitous markers of MDR include the multidrug transporters, P-glycoprotein and the Multidrug Resistance Associated Protein. These transporters limit the intracellular delivery of drugs by virtue of drug efflux. We discovered that extracellular vesicles, microparticles (MPs), provide a novel pathway for the dissemination of MDR in vitro and in vivo. We also showed that MPs plays a role in regulating the dominance of deleterious traits in cancer cell populations.

Methods: MPs were isolated from MDR cells by differential centrifugation. Western blot and flow cytometry were used to detect resistance proteins on MPs and on drug-sensitive recipient cells following MP co-culture. The nucleic acid content was determined using qPCR and miRNA Affymetrix arrays. Functionality of acquired proteins and MP drug sequestration were established using dye exclusion techniques.

Results: MPs from MDR cells transfer resistance proteins to recipient cells, and confer MDR. The transfer of nucleic acid cargo re-templates the transcriptional landscape of recipient cells to reflect the donor cells. MPs sequester drugs through both passive and active mechanisms, providing a parallel pathway, further limiting drug exposure.

Conclusion: We describe a novel pathway whereby MPs mediate the intercellular transfer of resistance and regulate the dominance of cancer traits. This introduces a new paradigm in clinical oncology and provides new therapeutic targets for the circumvention of MDR.

This research is funded by the NHMRC (APP1007613)