Abstract 1151: Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery

Abstract Introduction: Castration-resistant prostate cancer (CRPC) has poor response to androgen deprivation therapy, which is caused by a sustained androgen receptor (AR) signal and therefore is considered as an incurable disease. MicroRNA let-7c has been implied as a tumor suppressor in prostate cancer by antagonizing AR expression and activity. In addition to cancer cells, our group previously also demonstrated that downregulation of let-7c by cancer-associated mesenchymal stem cells (MSCs) triggering a reactive stromal response to facilitate prostate cancer growth and metastasis (PLoS ONE 8(8): e71637). Accordingly, treatment with exogenous let-7c would target both cancer cells and their associated MSCs and could be an attractive therapeutic approach to effectively inhibit CRPC recurrence and prevent metastasis. Exosomes are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication, which have the absolute predominance in biocompatibility for clinical applications in drug delivery and gene therapy. Objective: By taking the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of using MSC-derived exosomes as an exogenous let-7c delivery system to target CRPC. Methods: Relative miRNA-let-7c expression across various prostate cancer cell lines was examined using q-RT PCR. MSC-derived exosomes were collected from a 3A6 human bone marrow-derived MSC cell line after cell transfection with pre-miR negative control and pre-miR-let-7c, and further characterized through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot. The effects of either naked or MSC-exosome encapsulated let-7c on CRPC cells was determined by WST-1 cell proliferation assay and wound healing migration assay. Results: MiRNA-let-7c expression was confirmed to be downregulated in most of CRPC-like cell lines compared with androgen-sensitive LNCaP. Overexpression of pre-miR-let-7 inhibited the ability of cell proliferation and migration of prostate cancer cells. Exogenous microRNAs can be successfully packaged into MSC-exosomes by cell transfection, without a disruption of exosome integrity. Treatment of CRPC-like PC3 (AR-negative) and CWR22r-v1 (AR-positive) cells with MSC-exosome encapsulated let-7c effectively delivered let-7c into cells and resulted in a significant reduction in cancer cell growth and metastasis in vitro. Conclusion: Herein, we have provided in vitro evidences to prove the concept that microRNA let-7c is a potential therapeutic intervention for CRPC, as well as MSC-derived exosomes can serve as a therapeutic let-7c delivery system to target the CRPC. Further in vivo validation of distribution and therapeutic efficacy of MSC-exosome-delivered let-7c in CRPC xenograft mouse model is currently being explored. Citation Format: Ida Kurniawati, Chia-Yen Hsueh, Shian-Ying Sung, Chia-Ling Hsieh. Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1151.