LAUSR

Introduction: Mesenchymal Stem Cells(MSCs) are multipotent stromal cells that are known to engraft into tumours, raising their potential as tumour-targeted delivery vehicles. MSCs secrete tiny vesicles known as exosomes, which contain genetic material including microRNAs, and are effectively taken up by recipient cells. This study aimed to characterise a tumour-suppressing microRNA, miR-379, and engineer MSCs to secrete exosomes enriched with the microRNA. Methods: The mechanism of action of miR-379 In Vivo was determined through lentivirus-mediated upregulation of miR-379 in breast tumours, and analysis of changes in tumour angiogenesis, proliferation and progression. Subsequently, MSCs were engineered with lenti-379 and any impact on MSC migration, proliferation and morphology was assessed. MSC-secreted exosomes were isolated and characterised using Transmission Electron Microscopy(TEM) and Western Blot. The exosomal microRNA content was analysed by RQ-PCR, and transfer between cell populations visualised using confocal microscopy. Results: While elevated miR-379 expression did not impact tumour size In Vivo, an increase in tumour necrosis and decrease in invasion was observed. MSCs were successfully transduced with miR-379, resulting in a distinct change in cell morphology. Despite this, MSC-379 cells maintained inherent tumour-targeted migratory capacity, with no impact on proliferation observed. MSC-379 derived exosomes were 30-120nm in size and expressed the exosome-associated protein CD63. A 5-fold increase in miR-379 was observed in engineered exosomes. Successful transfer of RFP-labelled MSC-derived exosomes to breast cancer cells was visualised using confocal microscopy. Conclusion: Engineering tumour-targeted MSCs to secrete exosomes enriched with miR-379 holds exciting potential as a novel therapy for breast cancer. Citation Format: O9Brien KP, Khan S, Thompson K, Joyce D, Lalor P, Dockery P, Ingoldsby H, Kerin MJ, Dwyer RM. Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-04-01.