Therapeutic strategies targeting “tumor-educated platelets” (TEPs) and platelet-tumor interactions by key signaling pathways (ITAM, P2Y12) may reduce metastasis and cancer. Using a TEP gene expression dataset originally created to study swarm intelligence-enhanced detection of lung cancer cells (GSE89843), we did do extensive transcriptome analysis to integrate these data with directed protein-protein interactions and build a TEP-specific signaling network. We analyze network topology and controllability and identify critical and indispensable nodes as well as high-weight, usually high-score nodes. We reconstruct (pharmacological) controllable subnetworks of TEP signaling, which we then explore for drugs targets. We found 111 upregulated and 108 downregulated genes compared to control platelets, enriched in pathways related to extracellular matrix interactions, cytoskeleton organization, immune signaling, and platelet activation. Ribosomal function, apoptosis, and immune signaling were among the downregulated processes, highlighting unique TEP profiles in non-small cell lung cancer (NSCLC). Our integrative analysis of TEPs in NSCLC reveals key transcriptional and network-based alterations harmful for the cancer patient. Using four complementary strategies, we identified five high-confidence genes, ITGA2B, FLNA, GRB2, FCGR2A, and APP, as central to TEP signaling. These can be targeted by FDA-approved drugs. Fostamatinib, a SYK inhibitor, emerged as top candidate drugs to disrupt ITAM-mediated platelet activation selectively, metastasis promoting metalloprotease and cytoskeletal targets influencing adhesion were also identified. A low-dose combination therapy of fostamatinib, Aducanumab, and acetylsalicylic acid (aspirin) may control TEP effects. In conclusion, our pre-clinical in silico approach revealed FDA-approved drugs that allow therapeutic targeting of metastasis-promoting TEPs and target NSCLC at the same time.
Osmanoğlu et al. (Thu,) studied this question.