Abstract 2640: Prevention of distant metastasis by disrupting the CTC-platelet interaction
Authors: Lei Zhu, Nina Wang, Ting Jiang, Louisa Channon, Lena Lemmer, Dominic Helm, Sebastian Schölch
Journal: Cancer Research (2025)

Abstract Circulating tumor cells (CTCs) are the primary mediators of hematogenous metastasis. During their journey in circulation, CTCs actively recruit platelets (PLTs) to form a protective cloak that facilitates immune evasion, enhances survival under shear stress, and promotes vascular adhesion and extravasation. We identified Neuraminidase 1 (NEU1) as a pivotal regulator of CTC-PLT interactions through its control of α2, 6-sialylation, a critical post-translational protein modification that mediates PLT recruitment. We observed that diminished NEU1 expression in CTCs is associated with elevated sialylation, increased platelet cloaking, and poor prognosis in gastrointestinal cancer patients. This suggests that CTC sialylation drives PLT-mediated immune evasion and correlates with metastatic efficiency. Glycosylation profiling of CTCs from genetically engineered mouse models revealed a dynamic interplay in which NEU1 regulates α2, 6-sialylation on the extracellular domains of glycoproteins. CRISPR-mediated knockout of NEU1 in tumor cells significantly enhanced sialylation, transendothelial migration, and metastatic seeding, whereas NEU1 overexpression suppressed platelet cloaking, inhibited CTC-PLT clustering, and reduced metastasis in vivo. NEU1 depletion increased metastatic efficiency, as evidenced by elevated proliferation of PLT-associated tumor cells in primary and metastatic tissues. Glycoproteomic analyses identified fibronectin 1 (FN1) as a potential NEU1-regulated, α2, 6-sialylated target, further linking glycosylation changes to tumor progression. These findings establish a mechanistic connection between NEU1, CTC glycosylation, and PLT interactions, highlighting the functional significance of α2, 6-sialylation in driving metastasis. To explore therapeutic potential, we investigate dual strategies targeting NEU1-mediated sialylation and CTC-PLT interactions. Preliminary experiments suggest that combining desialylation treatments with chemotherapy may effectively limit metastatic seeding by reducing CTC sialylation and disrupting PLT cloaking, thereby interfering with key steps of the metastatic cascade. Ongoing studies aim to validate these findings and assess their potential for clinical translation. Our findings underscore the central role of sialic acid metabolism in regulating CTC-PLT dynamics and establish NEU1 as a key regulator of this process. Unraveling how NEU1-mediated sialylation drives platelet cloaking and metastasis, this work opens avenues for novel therapeutic interventions to disrupt CTC-driven dissemination, thus reducing the metastatic burden and improving outcomes in cancer patients. Citation Format: Lei Zhu, Nina Wang, Ting Jiang, Louisa Channon, Lena Lemmer, Dominic Helm, Sebastian Schölch. Prevention of distant metastasis by disrupting the CTC-platelet interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2640.