Mombach, J. C. M. | Search bioRxiv

bioRxiv2023

PseudoCell: A collaborative network for in silico prediction of regulatory pathways

Premature cellular senescence is a pivotal process in aging and age-related diseases, triggered by various stressors. However, this is not a homogeneous phenotype, but a heterogeneous cellular state composed of multiple senescence programs with different compositions. Therefore, understanding the complex dynamics of senescence programs requires a systemic approach. We introduce PseudoCell, a multi-valued logical regulatory network designed to explore the molecular intricacies of premature senescence. PseudoCell integrates key senescence signaling pathways and molecular mechanisms, offering a versatile platform for investigating diverse premature senescence programs initiated by different stimuli. Validation through simulation of classical senescence programs, including oxidative stress-induced senescence (OSIS) and oncogene-induced senescence (OIS), demonstrates its ability to replicate molecular signatures consistent with empirical data. Additionally, we explore the role of CCL11, a novel senescence-associated molecule, through simulations that reveal potential pathways and mechanisms underlying CCL11-mediated senescence induction. In conclusion, PseudoCell provides a systematic approach to dissecting premature senescence programs and uncovering novel regulatory mechanisms.

bioinformatics↗

bioRxiv2017

Network integration of multi-tumour omics data suggests novel targeting strategies

We characterize different tumour types in the search for multi-tumour drug targets, in particular aiming for drug repurposing or novel drug combinations. Starting from 11 tumour types from The Cancer Genome Atlas, we obtain three clusters based on transcriptomic correlation profiles. A network-based analysis, integrating gene expression profiles and protein interactions of cancer-related genes, allowed us to define three cluster-specific signatures, with genes belonging to NF-B signaling, chromosomal instability, ubiquitin-proteasome system, DNA metabolism, and apoptosis biological processes. These signatures have been characterized by different approaches based on mutational, pharmacological and clinical evidences, demonstrating the validity of our selection. Moreover, we defined new pharmacological strategies validated by in vitro experiments that showed inhibition of cell growth in two tumour cell lines, with significant synergistic effect. Our study thus provides a list of genes and pathways with the potential to be used, singularly or in combination, for the design of novel treatment strategies.

systems biology↗