Platelets, traditionally known as mediators of hemostasis, are also recognized as active regulators of immunity, inflammation, and tumour progression. Despite their broad functional repertoire, the molecular mechanisms underlying platelet activation and secretory behaviour remain insufficiently defined. Recent research has shown that platelets contain both constitutive proteasome and immunoproteasome, complexes previously thought to function primarily in nucleated immune cells. This dissertation investigates how these proteolytic systems shape platelet biology and influence platelet-driven immune and tumour interactions.
We highlighted the clinical relevance of platelet proteasome function by quantifying thrombocytopenia in multiple myeloma patients treated with proteasome inhibitors. A comprehensive meta-analysis shows that proteasome inhibition significantly increases the incidence of thrombocytopenia, with risk modulated by the specific inhibitor and dosage used. These findings demonstrate that therapeutic targeting of the proteasome has substantial hematologic consequences and suggest that altered proteasome activity may influence platelet function. To explore this mechanistically, we characterized proteasome and immunoproteasome activity in human platelets and documented considerable interindividual variability in proteasomal profiles. This heterogeneity suggests that the proteasome system contributes to donor-specific differences in platelet responsiveness and secretory capacity. Further work shows that the immunoproteasome modulates platelet secretion in a subunit-specific manner. Unlike nucleated cells, platelets do not upregulate immunoproteasome components in response to inflammatory cytokines, indicating that their proteasomal composition is fixed during megakaryopoiesis. Selective inhibition of catalytic subunits enhances dense-granule secretion while preserving aggregation, demonstrating that the immunoproteasome fine-tunes platelet secretory responses without compromising primary hemostatic function. Proteomic analyses reveal corresponding shifts in secreted proteins linked to metabolic and mitochondrial pathways, suggesting that immunoproteasome activity influences platelet bioenergetics and platelet communication. Although the downstream effects on immune cell activation show donor-dependent variability, the overall data establish the immunoproteasome as a previously underappreciated regulator of platelet-derived immune signalling. Platelets with selectively inhibited immunoproteasome subunits release factors that profoundly influence breast cancer cell behaviour. In particular, suppression of the β1i subunit generates a secretory profile that enhances migration of triple-negative breast cancer cells, increases angiogenic signalling, and upregulates epithelial-mesenchymal transition-related markers. These findings show that the platelet immunoproteasome directly shapes tumour-relevant paracrine cues and may influence metastatic progression.
Ultimately this dissertation establishes the proteasome and immunoproteasome as regulators of platelet signalling, secretion, and intercellular communication, with broad implications for immune regulation and cancer biology. By linking clinical data on proteasome inhibitor-associated thrombocytopenia to detailed mechanistic and functional studies, it provides a comprehensive view of how proteasomal pathways govern platelet behaviour and highlights new opportunities for modulation of platelet-tumour interactions.
|
