Cell Reports (Aug 2017)
Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells
- 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
Affiliations
- Theodoros I. Roumeliotis
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Steven P. Williams
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Emanuel Gonçalves
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Clara Alsinet
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Martin Del Castillo Velasco-Herrera
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Nanne Aben
- Division of Molecular Carcinogenesis, Computational Cancer Biology, the Netherlands Cancer Institute, Amsterdam 1066, the Netherlands
- Fatemeh Zamanzad Ghavidel
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Magali Michaut
- Division of Molecular Carcinogenesis, Computational Cancer Biology, the Netherlands Cancer Institute, Amsterdam 1066, the Netherlands
- Michael Schubert
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Stacey Price
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- James C. Wright
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Lu Yu
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Mi Yang
- Faculty of Medicine, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen 52057, Germany
- Rodrigo Dienstmann
- Computational Oncology, Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
- Justin Guinney
- Computational Oncology, Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
- Pedro Beltrao
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Alvis Brazma
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Mercedes Pardo
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Oliver Stegle
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- David J. Adams
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Lodewyk Wessels
- Division of Molecular Carcinogenesis, Computational Cancer Biology, the Netherlands Cancer Institute, Amsterdam 1066, the Netherlands
- Julio Saez-Rodriguez
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
- Ultan McDermott
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- Jyoti S. Choudhary
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
- DOI
- https://doi.org/10.1016/j.celrep.2017.08.010
- Journal volume & issue
-
Vol. 20,
no. 9
pp. 2201 – 2214
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.
Keywords
- proteomics
- TMT
- protein complexes
- networks
- phosphorylation
- mutations
- CRISPR/cas9
- colorectal cancer
- cell lines
- drug response