Transcriptomic and functional characterization of megakaryocytic-derived platelet-like particles: impaired aggregation and prominent anti-tumor effects

• Published in: Platelets (Edinburgh) 2025-12, Vol.36 (1), p.2449344
• Main Authors: Garofano, Kaitlin, Mariani, Vera, Rashid, Kameron, Suwunnakorn, Sumanun, Sidahmed, Alfateh, Horvath, Anelia, Maggirwar, Sanjay B, O'Brien, Travis J, Perera, Minoli A, Whalen, Michael, Lee, Norman H
• Format: Article
• Language: English
• Subjects: Apoptosis; Blood Platelets - metabolism; cancer biology; cell invasion; Cell Line, Tumor; functional genomics; Humans; MDA-PCa-2b cells; Megakaryocytes - metabolism; platelet; Platelet Aggregation; Signal Transduction; Transcriptome
• ISSN: 0953-7104; 1369-1635; 1369-1635
• DOI: 10.1080/09537104.2024.2449344

Platelet-like particles (PLPs), derived from megakaryocytic cell lines MEG-01 and K-562, are widely used as a surrogate to study platelet formation and function. We demonstrate by RNA-Seq that PLPs are transcriptionally distinct from platelets. Expression of key genes in signaling pathways promoting platelet activation/aggregation, such as the PI3K/AKT, protein kinase A, phospholipase C, and α-adrenergic and GP6 receptor pathways, was missing or under-expressed in PLPs. Functionally, PLPs do not aggregate following epinephrine, collagen, or ADP stimulation. While PLPs aggregated in response to thrombin, they did not display enhanced expression of surface markers P-selectin and activated α β , in contrast to platelets. We have previously demonstrated that platelets physically couple to MDA-PCa-2b and RC77T/E prostate cancer (PCa) cells via specific ligand-receptor interactions, leading to platelet-stimulated cell invasiveness and apoptotic resistance, and reciprocal cell-induced platelet aggregation. In contrast, PLP interactions with PCa cells inhibited both cell invasion and apoptotic resistance while failing to promote PLP aggregation. Moreover, PLPs reduced platelet-PCa cell interactions and antagonized platelet-stimulated oncogenic effects in PCa cells. RNA-Seq analysis identified candidate ligand-transmembrane protein combinations involved in anti-tumorigenic signaling of PLPs to PCa cells. Antibody neutralization of the TIMP3-MMP15 and VEGFB-FGFR1 signaling axes reversed PLP-mediated anti-invasion and apoptotic sensitization, respectively. In summary, PLPs lack many transcriptomic, molecular and functional features of platelets and possess novel anti-tumorigenic properties. These findings indicate that PLPs may have a potential therapeutic role in targeting and disrupting the oncogenic signaling between platelets and cancer cells, offering a new avenue for anti-cancer strategies.