Network Rewiring in Cancer: Applications to Melanoma Cell Lines and the Cancer Genome Atlas Patients

Abstract

Genes do not work in isolation, but rather as part of networks that have many feedback and redundancy mechanisms. Studying the properties of genetic networks and how individual genes contribute to overall network functions can provide insight into genetically-mediated disease processes. Most analytical techniques assume a network topology based on normal state networks. However, gene perturbations often lead to the rewiring of relevant networks and impact relationships among other genes. We apply a suite of analysis methodologies to assess the degree of transcriptional network rewiring observed in different sets of melanoma cell lines using whole genome gene expression microarray profiles. We assess evidence for network rewiring in melanoma patient tumor samples using RNA-sequence data available from The Cancer Genome Atlas. We make a distinction between “unsupervised” and “supervised” network-based methods and contrast their use in identifying consistent differences in networks between subsets of cell lines and tumor samples. We find that different genes play more central roles within subsets of genes within a broader network and hence are likely to be better drug targets in a disease state. Ultimately, we argue that our results have important implications for understanding the molecular pathology of melanoma as well as the choice of treatments to combat that pathology.

Dynamic and Thermodynamic Models of Adaptation

“…A detailed analysis of rewiring correlation networks of gene expressions was presented in [41] for melanoma. The authors argue that an approach to analyzing molecular pathophysiological processes based only on gene expression values cannot succeed in predicting the potential effect of a drug because it does not solve the important problem of the relationship between genes.…”

Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

“…This finding raises a further question: how precisely can oncogenic MAPK signaling be repressed while receptor- mediated MAPK signaling remains active? The accepted explanation is that the cell signaling has become “rewired” in adapted cells (Ding et al , 2018; Lee et al , 2012; Wei et al , 2020).…”

Dynamic rewiring of biological activity across genotype and lineage revealed by context-dependent functional interactions

“…We hypothesized that mutations in specific genes, and more broadly the genetic and epigenetic state of cells, could rewire these coessentiality networks, and that disentangling this rewiring could elucidate the biological and therapeutic implications of genetic lesions and tissue-specific diseases. Context-specific interaction rewiring or differential network analysis is a useful tool for understanding how fixed genomes can emerge into heterogeneous cellular and tissue morphologies and phenotypes (Ding et al, 2018; Ideker and Krogan, 2012; Kim et al, 2012). Previously, studies of comparison of coexpression between two contexts selected from a pool were introduced to discover differentially regulated interactions by specific context (Cho et al, 2009; Hsu et al, 2015; Lui et al, 2015).…”