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

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. Since the chaperome is among the central components of the PN, we focused on the chaperome in our study by utilizing 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 analyses 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.Author summary: Protein homeostasis, or proteostasis, is maintained by the proteostasis network (PN), an intricately regulated modular network of interacting processes that evolved to balance the native proteome, supporting cellular and organismal health throughout lifespan. Imbalances and collapse of cellular proteostasis capacity, the capacity to buffer against cytotoxic damage and stress, is increasingly implicated in some of the most challenging diseases of our time, including neurodegeneration and cancers. The systems-level PN alterations in these diseases are not understood to date. Here, we address this challenge, focussing on the human chaperome, the ensemble of chaperones and co-chaperones, which represents a central conserved PN functional arm. We devised a novel data dimensionality reduction approach enabling quantitative contextual visualization of chaperome alterations in the heterogeneous spectrum of cancers based on gene expression data from thousands of patient biopsies. We developed Proteostasis Profiler (Pro2), a new web-tool enabling intuitive visualisation of cancer chaperome deregulation maps. We stratify two cancer groups based on diverging chaperome deregulation and highlight similarities between cancer and stem cell proteostasis. Our study also exposes drastically opposed shifts between cancers and neurodegenerative diseases. Collectively, this study sets the stage for a systematic global analysis of PN alterations across the human diseasome.