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Comparative network-based analysis of toll-like receptor agonist, L-pampo signaling pathways in immune and cancer cells

ABSTRACT: Toll-like receptors (TLRs) are critical immune components to stimulate immune responses against various infections. Recently, TLR agonists have emerged as a promising way to activate anti-tumor immunity. L-pampo, a TLR1/2 and TLR3 agonist, induces robust humoral and cellular immune responses but also causes cancer cell death. In this study, we investigated the L-pampo-induced signal pathways in immune and cancer cells and how they interact with TLRs and cancer-related pathways. First, we constructed a template network with differentially expressed genes and influential genes using the weighted gene co-expression network analysis (WGCNA). Next, we obtained perturbed modules using the same method and extracted core subnetworks from the modules by running Walktrap. Finally, we attempted to link the core subnetworks for reconstructing major molecular signals regarding the response to L-pampo utilizing a shortest path finding algorithm, TOPAS. Our analysis revealed that the key molecular processes were PI3K-AKT, JAK-STAT, and oxidative phosphorylation (OXPHOS) with reactive oxygen species (ROS) in immune and cancer cells. Notably, the OXPHOS process may be the crucial regulator for the differential responses of L-pampo between cancer cells of different tissue types. Our computational approaches can be applied to similar research for inferring underlying molecular mechanisms using complex gene expression profiles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264131 | GEO | 2024/07/26

REPOSITORIES: GEO

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Project description:With the rapidly increasing availability of genomic data and ensuing identification of disease associated mutations, the determination of molecular mechanisms by which such mutations affect biochemical processes and phenotypes remains a major challenge. In this study we developed and applied a multilayered proteomic workflow to explore how genetic lesions modulate the modular proteome to alter functional phenotypes. Using this workflow we determined how expression of a panel of disease-associated mutations in the Dyrk2 protein kinase altered the composition, topology and activity of the multifunctional protein complex assembled around Dyrk2 and the phosphoproteomic state of the respective cells. We found that the selected cancer-related Dyrk2 mutations caused, to a differing extent, disassembly of the catalytic kinase core complex and caused disruption of interactions within the Dyrk2 core or with other cellular modules. This is exemplified by the nuclear pore associated Y-complex which we identified as new interactor of Dyrk2. We further found that the altered protein-protein interactions caused by the mutations are associated with topological changes and with changes in posttranslational modifications in the mutated kinase modules. Finally, we observed that the expression of each tested cancer-related mutation created a specific phosphoproteomic footprint including altered phosphorylation of known cancer-associated proteins, thus linking Dyrk2 mutations with cancer-related biochemical processes. Overall we developed an integrated, multilayered proteomic workflow to study how specific genomic mutations affect the modular proteome. Applying it to mutations in the Dyrk2 kinase we discover multiple mutation-specific, significant, pleiotropic and functionally relevant changes, highlighting the large plasticity of molecular responses to genomic lesions. The established workflow is generically applicable and will contribute to a better understanding of the molecular mechanisms that translate genomic alterations into (disease) phenotypes.

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Comparative network-based analysis of toll-like receptor agonist, L-pampo signaling pathways in immune and cancer cells

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