Shuangyi Cai, Thomas Hu, Abhijeet Venkataraman, Felix G. Rivera Moctezuma, Efe Ozturk, Nicholas Zhang, Mingshuang Wang, Tatenda Zvidzai, Sandip Das, Adithya Pillai, Frank Schneider, Suresh S. Ramalingam, You-Take Oh, Shi-Yong Sun, Ahmet F. Coskun
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Spatially resolved subcellular protein–protein interactomics in drug-perturbed lung-cancer cultures and tissues
Protein–protein interactions (PPIs) regulate signalling pathways and cell phenotypes, and the visualization of spatially resolved dynamics of PPIs would thus shed light on the activation and crosstalk of signalling networks. Here we report a method that leverages a sequential proximity ligation assay for the multiplexed profiling of PPIs with up to 47 proteins involved in multisignalling crosstalk pathways. We applied the method, followed by conventional immunofluorescence, to cell cultures and tissues of non-small-cell lung cancers with a mutated epidermal growth-factor receptor to determine the co-localization of PPIs in subcellular volumes and to reconstruct changes in the subcellular distributions of PPIs in response to perturbations by the tyrosine kinase inhibitor osimertinib. We also show that a graph convolutional network encoding spatially resolved PPIs can accurately predict the cell-treatment status of single cells. Multiplexed proximity ligation assays aided by graph-based deep learning can provide insights into the subcellular organization of PPIs towards the design of drugs for targeting the protein interactome.
期刊介绍:
Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.