Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells
Theodoros I. Roumeliotis (Wellcome Trust Sanger Institute)
Steven P. Williams (Wellcome Trust Sanger Institute)
Emanuel Gonçalves (European Molecular Biology Laboratory)
Clara Alsinet (Wellcome Trust Sanger Institute)
Martin Del Castillo Velasco-Herrera (Wellcome Trust Sanger Institute)
N.N. Aben (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Fatemeh Zamanzad Ghavidel (European Molecular Biology Laboratory)
Magali Michaut (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Michael Schubert (European Molecular Biology Laboratory)
Stacey Price (Wellcome Trust Sanger Institute)
L. F.A. Wessels (TU Delft - Pattern Recognition and Bioinformatics, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
G.B. More authors (External organisation)
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Abstract
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
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