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The genetic landscape of a human cell reveals conserved topology and principles of genetic networks

ABSTRACT: We generated a genome-scale, genetic interaction network from the analysis of more than 5 million double mutants in the haploid human cell line, HAP1. The network comprises ~90,000 negative and positive genetic interactions, including thousands of extreme synthetic lethal and genetic suppression interactions. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Systematic comparative analyses showed that the general principles and topology of genetic networks are conserved from yeast to humans. A genetic interaction network mapped in a single genetic background complements the DepMap cancer cell co-essentiality network, recapitulating many of the same functional connections and also capturing unique functional information to reveal roles of previously uncharacterized genes and molecular determinants of specific cancer cell line genetic dependencies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296341 | GEO | 2026/05/07

REPOSITORIES: GEO

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Project description:Aberrant activities of fourteen Eph receptor tyrosine kinases (RTKs) and their eight ephrin ligands are often observed in human malignancies, where they control cancer development, progression, and aggressiveness. While multiple attempts have been made to target Eph receptors in tumors, their effectiveness has been hindered by distinct contexts in which these proteins operate to enhance or suppress the disease. One of the strategies to overcoming this challenge is to define the molecular landscape/genetic interactions (GIs) associated with pro- and anti-malignant activities of Ephs and ephrins, as this should outline context-specific genetic dependencies associated with these molecules. Here, we used a multi-step bioinformatics analysis of the TCGA database and the DepMap gene essentiality data from cancer cell lines to construct a network of GIs of Ephs and ephrins in human malignancies. Validation of the relevance of this network was centered on an unusual Eph receptor EPHB6, which is innately kinase-incompetent, but nevertheless, actively controls aggressiveness and tumor initiation in several cancer types. To select the most relevant GI from the generated network, we performed genome-wide screening and EPHB6 BioID analysis. While, the BioID approach pointed towards EPHB6 interactions with several RTKs, including all kinase-active members of the EGFR/ErbB class, its integration with shRNA screening and computationally predicted GIs, unambiguously pointed towards EGFR as a key EPHB6 partner. Indeed, our further experiments confirmed EPHB6 interactions with all kinase-competent ErbBs, including EGFR, and revealed its ability to modulate EGF-induced EGFR tyrosine phosphorylation and downstream signaling. This ultimately, enhanced proliferation of cancer cells, culminating in efficient tumor development. In agreement, we found high levels of EGFR to positively correlate with higher EPHB6 expression in several tumor types. Taken together, these observations indicate that EPHB6 should serve as an effective target in tumors with high EGFR levels and that co-targeting these receptors might provide therapeutic benefits. More importantly, these experiments provide a strong support for the relevance of our computational strategy and suggest that the generated network describing GIs of Eph receptors and their ligands is a valuable resource that can be used for developing new treatment approaches aiming to hunt these proteins in human malignancies.

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The genetic landscape of a human cell reveals conserved topology and principles of genetic networks

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