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A systematic atlas of chaperome deregulation topologies across the human cancer landscape

View ORCID ProfileAli Hadizadeh Esfahani, Angelina Sverchkova, View ORCID ProfileJulio Saez-Rodriguez, View ORCID ProfileAndreas A Schuppert, View ORCID ProfileMarc Brehme
doi: https://doi.org/10.1101/122044
Ali Hadizadeh Esfahani
1Joint Research Center for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, 52074 Aachen, Germany
2Aachen Institute for Advanced Study in Computational Engineering Science (AICES), RWTH Aachen University, 52062 Aachen, Germany
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  • ORCID record for Ali Hadizadeh Esfahani
Angelina Sverchkova
1Joint Research Center for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, 52074 Aachen, Germany
3Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Julio Saez-Rodriguez
1Joint Research Center for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, 52074 Aachen, Germany
3Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
4European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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Andreas A Schuppert
1Joint Research Center for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, 52074 Aachen, Germany
2Aachen Institute for Advanced Study in Computational Engineering Science (AICES), RWTH Aachen University, 52062 Aachen, Germany
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Marc Brehme
1Joint Research Center for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, 52074 Aachen, Germany
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  • For correspondence: brehme@combine.rwth-aachen.de
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Abstract

Proteome balance is safeguarded by the proteostasis network (PN), an intricately regulated network of conserved processes that evolved to maintain native function of the diverse ensemble of protein species, ensuring cellular and organismal health. Proteostasis imbalances and collapse are implicated in a spectrum of human diseases, from neurodegeneration to cancer. The characteristics of PN disease alterations however have not been assessed in a systematic way. Zooming in on the chaperome as a central PN component we turned to a curated functional ontology of the human chaperome that we connect in a high-confidence physical protein-protein interaction network. Challenged by the lack of a systems-level understanding of proteostasis alterations in the heterogeneous spectrum of human cancers, we assessed gene expression across more than 10,000 patient biopsies covering 22 solid cancers. We derived a novel customized Meta-PCA dimension reduction approach yielding M-scores as quantitative indicators of disease expression changes to condense the complexity of cancer transcriptomics datasets into quantitative functional network topographies. We confirm upregulation of the HSP90 family and also highlight HSP60s, Prefoldins, HSP100s, ER- and mitochondria-specific chaperones as pan-cancer enriched. Our analysis also reveals a surprisingly consistent strong downregulation of small heat shock proteins (sHSPs) and we stratify two cancer groups based on the preferential upregulation of ATP-dependent chaperones. Strikingly, our analysis highlight similarities between stem cell and cancer proteostasis, and diametrically opposed chaperome deregulation between cancers and neurodegenerative diseases. We developed a web-based Proteostasis Profiler tool (Pro2) enabling intuitive analysis and visual exploration of proteostasis disease alterations using gene expression data. Our study showcases a comprehensive profiling of chaperome shifts in human cancers and sets the stage for a systematic global analysis of PN alterations across the human diseasome towards novel hypotheses for therapeutic network re-adjustment in proteostasis disorders.

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Posted May 04, 2017.
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A systematic atlas of chaperome deregulation topologies across the human cancer landscape
Ali Hadizadeh Esfahani, Angelina Sverchkova, Julio Saez-Rodriguez, Andreas A Schuppert, Marc Brehme
bioRxiv 122044; doi: https://doi.org/10.1101/122044
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A systematic atlas of chaperome deregulation topologies across the human cancer landscape
Ali Hadizadeh Esfahani, Angelina Sverchkova, Julio Saez-Rodriguez, Andreas A Schuppert, Marc Brehme
bioRxiv 122044; doi: https://doi.org/10.1101/122044

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