WEHI PhD Completion Seminar hosted by Dr Alexandra Garnham

Yimin Zhang
PhD Student – Bioinformatics Support Facility, Bioinformatics and Computational Biology division, WEHI

Integrative Transcriptomic and Proteomic Analyses of TNF Signalling Across Diseases and ADO Functional Knock-out Analysis

Davis Auditorium

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Including Q&A session               

Tumour necrosis factor (TNF; TNFα) is a pleiotropic pro-inflammatory cytokine that plays central roles in inflammation, cell proliferation and death, intercellular communication, and immune regulation. Dysregulated TNF signalling has been strongly implicated in the pathogenesis of autoimmune diseases and cancer. Although multiple TNF-related gene signatures have been proposed to predict patient survival or therapeutic response, many studies are limited by their focus on a single disease context, specific cell types, or single-omics datasets, and often rely on TNF gene knockout models that may not fully capture pathway dynamics.

To overcome these limitations, I integrated transcriptomic datasets derived from diverse cell types with proteomic data generated from TNF-treated cells to identify robust and generalizable molecular signatures of TNF signalling. From this framework, I derived a 9-gene transcriptomic signature that was validated across multiple publicly available datasets. The signature demonstrated highly reliable scoring performance compared with existing public TNF signatures and showed strong specificity for TNF signalling, effectively distinguishing TNF-driven responses from interferon-γ (IFNγ) signalling.

Clinical data showed the TNF score decreased in rheumatoid arthritis patients following TNF inhibitor (TNFi) therapy, supporting its biological relevance to pathway modulation. In cancer, high TNF score was associated with more tumour immune cell infiltration, highlighting its potential utility in characterizing tumour immune microenvironments.

Furthermore, previous studies reported that adenosine kinase (Ado), a metabolic enzyme that has also been identified as an oxygen sensor, when knocked out enables murine cells to escape TNF-dependent cell death. My integrated transcriptomic and proteomic analyses of Ado-deficient cells revealed that canonical TNF signalling was not attenuated. Instead, the expression changes were enriched in mitochondrial function, cellular metabolism, and protein synthesis. These findings suggest that further investigation is required to elucidate the mechanistic interplay between Ado and TNF pathways.

All welcome!