Synthetic lethality in large-scale integrated metabolic and regulatory network models of human cells

Synthetic lethality (SL) is a promising concept in cancer research. A wide array of computational tools has been developed to predict and exploit synthetic lethality for the identification of tumour-specific vulnerabilities. Previously, we introduced the concept of genetic Minimal Cut Sets (gMCSs), a theoretical approach to SL developed for genome-scale metabolic networks. The major challenge in our gMCS framework is to go beyond metabolic networks and extend existing algorithms to more complex protein-protein interactions. In this article, we take a step further and incorporate linear regulatory pathways into our gMCS approach. Extensive algorithmic modifications to compute gMCSs in integrated metabolic and regulatory models are presented in detail. Our extended approach is applied to calculate gMCSs in integrated models of human cells. In particular, we integrate the most recent genome-scale metabolic network, Human1, with 3 different regulatory network databases: Omnipath, Dorothea and TRRUST. Based on the computed gMCSs and transcriptomic data, we discovered new essential genes and their associated synthetic lethal for different cancer cell lines. The performance of the different integrated models is assessed with available large-scale in-vitro gene silencing data. Finally, we discuss the most relevant gene essentiality predictions based on published literature in cancer research.

Automated summary

Synthetic lethality is a promising concept in cancer research, and computational tools have been developed to predict and exploit it for identifying tumor-specific vulnerabilities. This article introduces the concept of genetic Minimal Cut Sets (gMCSs), which is a theoretical approach to synthetic lethality for genome-scale metabolic networks. By incorporating linear regulatory pathways, the authors extended the gMCS approach to complex protein-protein interactions and applied it to integrated models of human cells, discovering new essential genes and their associated synthetic lethal in cancer. The performance of different integrated models was assessed using large-scale in-vitro gene silencing data, and predictions were discussed based on published literature in cancer research.