Abstract A007: Development of a fibrinolytic platelet system to dissociate circulating tumor cell clusters

Abstract

Abstract Circulating tumor cell (CTC) clusters play a significant role in cancer metastasis. During metastasis, CTCs can travel in the bloodstream as individual cells or as clusters associated with fibrin and platelets (Palumbo et al., Blood 2000; Karpatkin and Pearlstein, Annals of Internal Medicine, 1981). The CTC clusters have a higher metastatic potential than individual tumor cells (Aceto, Cell 2014) due to the increased viability of tumor cells in clusters, the increased chance of large clusters arresting in small vessels, and the increased ability of clusters to form a metastatic niche at a distal location. As such, there is a need to develop methods to disperse CTC clusters. Previous work with urokinase-type plasminogen activator has shown initial success in reducing metastasis by dissociating cancer cell clusters (Choi et al., Cancer Res. 2015). However, there is another key component of this metastatic challenge, the interaction of CTCs with platelets. Platelets bind to the CTC surface which protects the CTC clusters from shear stress and immune detection, increasing their metastatic potential (Morris, Schnoor, and Papa, Biochim. Biophys. Acta BBA - Rev. Cancer 2022). However, these interactions also provide an approach to target CTC clusters. As such, the objective of this project is to develop a fibrinolytic platelet system to dissociate CTC clusters while also disrupting CTC-platelet interactions. For this approach, TPA was loaded onto two modified platelet systems: platelet decoys (Papa et al., Sci. Transl. Med. 2019) and lyophilized platelets (Schnoor and Papa, Front. Bioeng. Biotechnol. 2022). Each system was assessed to determine the surface receptor characteristics, drug loading, and interaction with tumor cells in vitro. The fibrinolytic activity of the systems was also characterized using a FRET based assay and the angiogenic effects of the systems were measured using a HUVEC tube formation assay. Furthermore, the ability of the system to dissociate cancer cell clusters in vitro was assessed for the first time using light transmission aggregometry. The results demonstrate that the TPA was successfully loaded onto both platelet decoys and lyophilized platelets while maintaining the fibrinolytic activity of the platelets. Furthermore, a high percentage of cancer cells interacted with the TPA-loaded carriers, which corresponds to the maintenance of key surface receptors such as GP IIb/IIIa. The data also demonstrates that the fibrinolytic platelet systems can successfully dissociate cancer cells in vitro. Currently, the effectiveness of these fibrinolytic platelet systems for preventing cancer cell metastasis is being assessed in vivo. Based on these results, this fibrinolytic platelet approach is a promising method to leverage platelet-CTC interactions to disperse CTC clusters and reduce metastasis. Citation Format: Brian Schnoor, Anne-Laure Papa. Development of a fibrinolytic platelet system to dissociate circulating tumor cell clusters [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A007.