Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Theodoros I. Roumeliotis, Steven P. Williams, Emanuel Gonçalves, Clara Alsinet, Martin Del Castillo Velasco-Herrera, Nanne Aben, Fatemeh Zamanzad Ghavidel, Magali Michaut, Michael Schubert, Stacey Price, James C. Wright, Lu Yu, Mi Yang, Rodrigo Dienstmann, Justin Guinney, Pedro Beltrao, Alvis Brazma, Mercedes Pardo, Oliver Stegle, David J. Adams, Lodewyk Wessels, Julio Saez-Rodriguez, Ultan McDermott, Jyoti S. Choudhary
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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Teaser

Roumeliotis et al. use in-depth proteomics to assess the impact of genomic alterations on protein networks in colorectal cancer cell lines. Cell-line-specific network signatures are inferred de novo by protein quantification profiles and ultimately expose the collateral and transcript-independent effects of detrimental mutations on protein complexes.


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