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 α2bβ3, 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.
Keywords: Apoptosis; MDA-PCa-2b cells; RC77T/E cells; cancer biology; cell invasion; functional genomics; platelet; platelet-like particle; prostate cancer.
What is the context? This study investigates the role of PLPs as substitutes for platelets in cancer biology, focusing on their ability to replicate platelet functions, particularly in stimulating cancer cell oncogenicity. Given the challenges of obtaining blood from volunteers in a timely manner and isolating a pure population of platelets, PLPs were explored as a potentially valuable alternative, though their biology as platelet surrogates remains untested.What is new? A comprehensive comparison of the transcriptome of PLPs compared to platelets.This research is the first to examine whether PLPs can communicate with cancer cells to promote oncogenicity and whether cancer cells can stimulate PLP aggregation. It provides novel insights into the potential of PLPs as a surrogate model in cancer studies.What is the impact? The study demonstrated that PLPs are transcriptionally distinct from platelets, lacking key genes in signaling pathways involved in platelet aggregation and cancer cell stimulation. Functionally, PLPs did not aggregate in response to agonists or cancer cells and instead exhibited anti-oncogenic effects on cancer cells. Moreover, PLPs functionally antagonized platelet-stimulated cancer cell oncogenicity. These findings suggest that PLPs could serve as a therapeutic tool to target and disrupt the oncogenic signaling between platelets and cancer cells.