Abstract 1728: Exosomal delivery of Fas-associated factor 1 (FAF1), a multifunctional tumor suppressor and genuine exosome cargo, effectively antagonizes tumor growth

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Abstract Introduction: Exosomes are extracellular vesicles of 30-150 nm and can stably deliver their cargos to the target with low immunogenicity and efficient transmission. FAF1 is a genuine exosome cargo and, therefore, loaded into exosomes without additional engineering. FAF1 is a tumor suppressive protein with multifunctional roles including death-promotion (both apoptosis and necrosis), cell cycle arrest, anti-inflammation, and anti-angiogenesis. FAF1 also inhibits metastasis via inhibition of TGF-β pathway. Moreover, FAF1 elicits low expression profiles in several types of cancer. Therefore, this study examined whether exosomal delivery of FAF1 is a plausible strategy for anti-tumor therapeutics. Methods: Stable suspension cells originated from HEK293 cells inducibly overexpressing FAF1 were screened using Tet on-off system to avoid cell death due to continuous FAF1 expression. FAF1 was overexpressed by Doxycycline induction and the amounts of FAF1 loaded on exosomes were normalized by exosome markers. The efficacy of exosomal FAF1 was evaluated in mouse xenograft models implanted with various human carcinoma cells. Results: Cell lines showing FAF1 expression with more than 3 fold of control cells were picked. Among FAF1-overexpressing cells, F5-3 cell line showing highest expression of exosomal FAF1 (showing 23 fold of FAF1 loading efficiency compared to parental cells) was used for exosomal source for in vivo experiments. Furthermore, F5-3 produced about 70 times of exosomal FAF1 when compared to that of HEK293 cell in the same volume of culture medium. The exosomal FAF1 produced in F5-3 cells inhibited tumor growth in various cancer types including lung, breast, liver, and pancreas in mouse xenograft models. In addition, exosomal FAF1 consistently demonstrated superior tumor-suppressive potential to soluble FAF1 in all tumors investigated in this study. Also, there were no serious side effects based on weight changes. Conclusion: This study demonstrated the tumor-suppressive potential of exosomal FAF1, demonstrating the feasibility of exosomal delivery of FAF1 as an efficient therapeutic measure. Furthermore, the selective and massive production properties of F5-3 cell realizes efficient and scalable production of exosomal FAF1. Citation Format: Jeong-Hoon Han, DaeHo Park, Bumjun Jung, Hyeong-Gwon Yoo, Kyung-Ok Cho, Eunhee Kim. Exosomal delivery of Fas-associated factor 1 (FAF1), a multifunctional tumor suppressor and genuine exosome cargo, effectively antagonizes tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1728.