Abstract
Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein–protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type. We found that first neighbours have at least as high degree, betweenness centrality and clustering coefficient as cancer-related proteins themselves, indicating a previously unknown central network position. We identified a complementary strategy for mutated and differentially expressed proteins, where the affect of differentially expressed proteins having smaller network centrality is compensated with high centrality first neighbours. These first neighbours can be considered as key, so far hidden, components in cancer rewiring, with similar importance as mutated proteins. These observations strikingly suggest targeting first neighbours as a novel strategy for disrupting cancer-specific networks. Remarkably, our survey revealed 223 marketed drugs already targeting first neighbour proteins but applied mostly outside oncology, providing a potential list for drug repurposing against solid cancers. For the very central first neighbours, whose direct targeting would cause several side effects, we suggest a cancer-mimicking strategy by targeting their interactors (second neighbours of cancer-related proteins, having a central protein affecting position, similarly to the cancer-related proteins). Hence, we propose to include first neighbours to network medicine based approaches for (but not limited to) anticancer therapies.
Highlights
Cancer is increasingly being considered as a “systems” disease, based on the observation that genetic changes and environmental influence rewire cellular networks during carcinogenesis.[1]
The other frequently studied group of genes in cancer biology is the set of differentially expressed genes (DEGs)
Encouraged by the finding that first neighbours of cancer-related proteins display a central network position, we investigated the relation between the network topology parameter of a cancerrelated protein and its first neighbour proteins. From this analysis we found that cancer-related proteins have two distinct topology patterns both in signalling and protein-protein interaction (PPI) networks: Mutated proteins have a higher or same degree, betweenness and clustering coefficient parameters compared to their first neighbours, while differentially expressed proteins have lower degree and betweenness than their first neighbours (Fig. 2a–b. and Supplementary Figs 4, 5; see Supplementary Table 6. for all detailed statistics)
Summary
Cancer is increasingly being considered as a “systems” disease, based on the observation that genetic changes and environmental influence rewire cellular networks during carcinogenesis.[1] Combinational classical chemotherapies, have been successfully applied against fast proliferating haematological cancers, such as acute myeloid or lymphoid leukaemia.[2] chemotherapy has only shown moderate effect against solid cancers like colon cancer or non-small cell lung cancer.[2] even today the most effective therapeutic solution against solid cancers is in many cases of surgery. The number of mutated genes, which are directly involved in carcinogenesis, is very low compared to those encoded by the whole genome. Vogelstein and his colleagues described 138 so called driver genes,[4] which are directly involved in cancer progression. Pathway analysis[6,7,8] showed that most driver genes are part of central
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