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Network Controllability Reveals Key Mitigation Points for Tumor-Promoting Signaling in Tumor-Educated Platelets
Özge Osmanoglu1, Elif Özer1, Shishir K Gupta1,2
1Functional Genomics & Systems Biology Group, Department of Bioinformatics, Biocenter, Am Hubland, University of Wuerzburg, 97074 Würzburg, Germany.
Abstract:
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 perform 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 (Gene symbols always given throughout the paper), ITGA2B, FLNA, GRB2, FCGR2A, and APP, as central to TEP signaling. These can be targeted by FDA-approved drugs. Fostamatinib, an SYK inhibitor, emerged as the top candidate drug 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 preclinical in silico approach revealed FDA-approved drugs that allow therapeutic targeting of metastasis-promoting TEPs and target NSCLC at the same time.
Insights
Targeting tumor-educated platelets (TEPs) with FDA-approved drugs like fostamatinib may reduce metastasis in non-small-cell lung cancer (NSCLC). This study identified key genes and drug combinations for TEP-specific therapies.
Area of Science:
- Oncology
- Hematology
- Bioinformatics
- Systems Biology
Background:
- Tumor-educated platelets (TEPs) play a crucial role in promoting cancer metastasis through complex signaling pathways.
- Existing therapeutic strategies often overlook the specific contributions of TEPs and their interactions with cancer cells.
- Identifying key molecular players and actionable targets within TEPs is essential for developing effective anti-cancer treatments.
Purpose of the Study:
- To perform a comprehensive transcriptome and network analysis of TEPs in non-small-cell lung cancer (NSCLC).
- To identify critical genes and signaling pathways within TEPs that drive cancer progression.
- To explore FDA-approved drugs and drug combinations for targeting TEPs and reducing metastasis.
Main Methods:
- Transcriptome analysis of TEP gene expression data (GSE89843) from NSCLC patients.
- Integration with protein-protein interaction data to construct a TEP-specific signaling network.
- Network topology and controllability analysis to identify key nodes and pharmacologically controllable subnetworks.
- Identification of high-confidence target genes and exploration of FDA-approved drugs.
Main Results:
- Identified 111 upregulated and 108 downregulated genes in TEPs, enriched in pathways related to extracellular matrix, cytoskeleton, immune signaling, and platelet activation.
- Highlighted unique TEP profiles in NSCLC, with downregulated ribosomal function, apoptosis, and immune signaling.
- Identified five high-confidence central genes (ITGA2B, FLNA, GRB2, FCGR2A, APP) and potential drug targets.
- Fostamatinib (SYK inhibitor) emerged as a top candidate to disrupt ITAM-mediated platelet activation; metalloprotease and cytoskeletal targets were also noted.
Conclusions:
- Integrative analysis reveals key transcriptional and network alterations in TEPs that are detrimental to NSCLC patients.
- FDA-approved drugs, including fostamatinib, Aducanumab, and aspirin, show potential for therapeutic targeting of metastasis-promoting TEPs.
- A preclinical in silico approach identified a promising combination therapy to simultaneously target TEPs and NSCLC, potentially reducing metastasis.
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