Biology subjects

Vukotic, R.

Publications and source records attributed to Vukotic, R..

3 recordsLinked to original sources

bioRxiv2026

The mutational landscape of innervation axes in cancer

The mutational landscape of neural innervation axes in cancer has garnered increasing attention due to their significant influence on tumorigenesis, metastasis, and treatment resistance. This study provides an overview of the alterations of neural signaling pathways based on multi-omics data analysis. In particular, we conducted a comprehensive analysis of mutations in key genes associated with neurotrophin signaling, norepinephrine and cholinergic pathways, alongside paracrine and synaptogenic factors. Our findings reveal that 65% of patients in a pancancer cohort exhibit at least one somatic alteration in these pathways, with neurotrophin genes being the most frequently altered. Notably, alterations in these genes (e.g., NGF) correlate with poor patient survival across various cancer types, suggesting their oncogenic potential. We also identified significant co-occurrence of mutations and differential expression patterns from both bulk and single-cell RNAseq data, indicating complex interactions among these pathways that contribute to tumor innervation and neuroplasticity. This study underscores the necessity of understanding the crosstalk between neural signaling and cancer biology to improve patient stratification based on mutational profiles and identify potential therapeutic targets. Further research utilizing advanced genomic techniques is essential to elucidate the mechanistic roles of these pathways in tumor innervation.

genomics↗

bioRxiv2025

Communication breakdown and evolution of the cancer cell

1We studied cell-cell interactions (CCIs) in large-scale transcriptomic datasets, which showed higher co-expression in cancer compared to healthy tissues. CCIs are more co-expressed than any other type of intracellular interaction and, likewise, they are the protein-protein interaction (PPI) class that is most co-evolved in sequenced genomes. Similar trends of stricter regulation and evolutionary pressure are observed when comparing extracellular versus intracellular interactions mediated by G protein Coupled Receptors (GPCRs), whose ligand interactions are also characterized by a higher mutational burden in later tumor stages when considering somatic mutations associated with tumor clonal evolution. CCIs undergo the most extensive rewiring of their tumor co-expression networks relative to healthy tissues, more so than any other PPI type, with a set of CCI hubs highly conserved across multiple tumor tissues, and a higher diversity on healthy ones. Cancer rewiring is also associated with the formation of recurrent circuits of co-expressed CCI pairs, represented by enriched network motifs such as triad or tetrad cliques. These act as integrative hotspots to facilitate the crosstalk of distinct processes and the interaction of the cancer cell with its tumor microenvironment (TME). Remarkably, many CCI circuits are significantly associated with patient survival and are predictive of patient response to immunotherapy. CCI circuits mapping to allograft rejection and inflammatory response inform immunotherapy response prediction, while those related to epithelial-mesenchymal transition are associated with poorer prognosis. Overall, we show that CCIs expression signatures could be effectively exploited to stratify patients and, at the same time, they highlight new combination therapeutic opportunities in personalized medicine settings.

bioinformatics↗

bioRxiv2023

The landscape of cancer rewired GPCR signaling axes

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes, which revealed that multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulated pathway activity signatures from metabolomics datasets, providing valuable surrogate information for GPCRs responding to organic ligands. We found that several GPCRs signaling components were significantly associated with patient survival in a cancer type-specific fashion. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many pairs involving receptor- biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including e.g., muscarinic, adenosine, 5-hydroxytryptamine and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it). SignificanceComprehensive analysis of GPCR extracellular network in cancer transcriptomics datasets reveals signaling axes associated to patient survival, whose targeting is associated with growth inhibition in cancer cell lines drug sensitivity assays.

bioinformatics↗