Abstract 1317: Exercise training prevents exosome mediated pre-metastatic niche formation in the liver

Abstract Introduction: Primary tumor cells release exosomes facilitating pre-metastatic niche formation in distant organs, initiating the process of metastasis. As metastasis is the main prognostic factor for patients, it is essential to understand the pre-metastatic niches and develop therapies to target them. It has been shown that Kupffer cells play an crucial role in the formation of pre-metastatic niche in the liver. We have recently shown that exercise training (ExT) alters the phenotype of Kupffer cells and attenuates tumor metastasis after surgery. Here, we hypothesize that ExT can interfere with exosome mediated pre-metastatic niches, hence decreasing metastasis. Methods: Eight-week-old male mice were randomized into sedentary and ExT group. Mice were pre-educated with cancer exosomes for 4 weeks to induce pre-metastatic niche and intra-splenically injected with murine colorectal cancer (MC38) cells. Tumor metastasis and growth was followed by 3 weeks. Results: Compared to the sedentary group, there was a significant decrease in metastatic nodules and hepatic tumor replacement in the ExT mice liver. To further study the effects of ExT, livers from both groups were harvested 4 weeks after exosome pre-education. We observed decrease in the uptake of tumor exosome, immune cells infiltration and fibronectin deposition in the ExT livers, which demonstrates less pre-metastatic niche formation. Bulk RNA sequencing was performed on Kupffer cells isolated from both groups. Ingenuity pathway analysis shows that Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling pathway was downregulated in EXT group, indicating less activation of Kupffer cells. Conclusions: These results indicate that exercise reduces pre-metastatic niche formation and tumor metastasis by affecting the interaction between cancer exosomes and Kupffer cells. In light of these findings, potential may exist to reduce exosome-induced liver pre-metastatic niches through the use of ExT as a nonpharmacologic therapy in patients with cancer. Citation Format: Ruiqi Yang, Tony Haykal, Celine Tohme, Ronghua Wang, Christof Kaltenmeier, David Geller, Hamza Yazdani, Samer Tohme. Exercise training prevents exosome mediated pre-metastatic niche formation in the liver [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 1317.