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, 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
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: CRISPR/cas9; TMT; cell lines; colorectal cancer; drug response; mutations; networks; phosphorylation; protein complexes; proteomics.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
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References
- Aken B.L., Achuthan P., Akanni W., Amode M.R., Bernsdorff F., Bhai J., Billis K., Carvalho-Silva D., Cummins C., Clapham P. Ensembl 2017. Nucleic Acids Res. 2017;45(D1):D635–D642.
- Allen J.D., Xie Y., Chen M., Girard L., Xiao G. Comparing statistical methods for constructing large scale gene networks. PLoS ONE. 2012;7:e29348.
- Beltrao P., Bork P., Krogan N.J., van Noort V. Evolution and functional cross-talk of protein post-translational modifications. Mol. Syst. Biol. 2013;9:714.
- Bertorelle R., Esposito G., Belluco C., Bonaldi L., Del Mistro A., Nitti D., Lise M., Chieco-Bianchi L. p53 gene alterations and protein accumulation in colorectal cancer. Clin. Mol. Pathol. 1996;49:M85–M90.
- Boland C.R., Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–2087.e3.
- Cairns B.R. Emerging roles for chromatin remodeling in cancer biology. Trends Cell Biol. 2001;11:S15–S21.
- Chan C.W.M., Wong N.A., Liu Y., Bicknell D., Turley H., Hollins L., Miller C.J., Wilding J.L., Bodmer W.F. Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1. Proc. Natl. Acad. Sci. USA. 2009;106:1936–1941.
- Chen Z., Shi T., Zhang L., Zhu P., Deng M., Huang C., Hu T., Jiang L., Li J. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016;370:153–164.
- Chen W.H., Lu G., Chen X., Zhao X.M., Bork P. OGEE v2: an update of the online gene essentiality database with special focus on differentially essential genes in human cancer cell lines. Nucleic Acids Res. 2017;45(D1):D940–D944.
- Costanzo M., VanderSluis B., Koch E.N., Baryshnikova A., Pons C., Tan G., Wang W., Usaj M., Hanchard J., Lee S.D. A global genetic interaction network maps a wiring diagram of cellular function. Science. 2016;353:aaf1420.
- Costello J.C., Heiser L.M., Georgii E., Gönen M., Menden M.P., Wang N.J., Bansal M., Ammad-ud-din M., Hintsanen P., Khan S.A., NCI DREAM Community A community effort to assess and improve drug sensitivity prediction algorithms. Nat. Biotechnol. 2014;32:1202–1212.
- Davis M.A., Larimore E.A., Fissel B.M., Swanger J., Taatjes D.J., Clurman B.E. The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. Genes Dev. 2013;27:151–156.
- De Sousa E Melo F., Wang X., Jansen M., Fessler E., Trinh A., de Rooij L.P., de Jong J.H., de Boer O.J., van Leersum R., Bijlsma M.F. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat. Med. 2013;19:614–618.
- Dix B., Robbins P., Carrello S., House A., Iacopetta B. Comparison of p53 gene mutation and protein overexpression in colorectal carcinomas. Br. J. Cancer. 1994;70:585–590.
- Forester C.M., Maddox J., Louis J.V., Goris J., Virshup D.M. Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1. Proc. Natl. Acad. Sci. USA. 2007;104:19867–19872.
- Garnett M.J., Edelman E.J., Heidorn S.J., Greenman C.D., Dastur A., Lau K.W., Greninger P., Thompson I.R., Luo X., Soares J. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–575.
- Garrison W.D., Battle M.A., Yang C., Kaestner K.H., Sladek F.M., Duncan S.A. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology. 2006;130:1207–1220.
- Gholami A.M., Hahne H., Wu Z., Auer F.J., Meng C., Wilhelm M., Kuster B. Global proteome analysis of the NCI-60 cell line panel. Cell Rep. 2013;4:609–620.
- Guinney J., Dienstmann R., Wang X., de Reyniès A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356.
- Hein M.Y., Hubner N.C., Poser I., Cox J., Nagaraj N., Toyoda Y., Gak I.A., Weisswange I., Mansfeld J., Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015;163:712–723.
- Hodges C., Kirkland J.G., Crabtree G.R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 2016;6:a026930.
- Hornbeck P.V., Zhang B., Murray B., Kornhauser J.M., Latham V., Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43:D512–D520.
- Huttlin E.L., Ting L., Bruckner R.J., Gebreab F., Gygi M.P., Szpyt J., Tam S., Zarraga G., Colby G., Baltier K. The BioPlex network: a systematic exploration of the human interactome. Cell. 2015;162:425–440.
- Iorio F., Knijnenburg T.A., Vis D.J., Bignell G.R., Menden M.P., Schubert M., Aben N., Gonçalves E., Barthorpe S., Lightfoot H. A landscape of pharmacogenomic interactions in cancer. Cell. 2016;166:740–754.
- Jones M.F., Hara T., Francis P., Li X.L., Bilke S., Zhu Y., Pineda M., Subramanian M., Bodmer W.F., Lal A. The CDX1-microRNA-215 axis regulates colorectal cancer stem cell differentiation. Proc. Natl. Acad. Sci. USA. 2015;112:E1550–E1558.
- Kaelin W.G., Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer. 2005;5:689–698.
- Kent W.J., Sugnet C.W., Furey T.S., Roskin K.M., Pringle T.H., Zahler A.M., Haussler D. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.
- Kuleshov M.V., Jones M.R., Rouillard A.D., Fernandez N.F., Duan Q., Wang Z., Koplev S., Jenkins S.L., Jagodnik K.M., Lachmann A. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–W97.
- Langfelder P., Horvath S. Eigengene networks for studying the relationships between co-expression modules. BMC Syst. Biol. 2007;1:54.
- Langfelder P., Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.
- Lei M., Tye B.K. Initiating DNA synthesis: from recruiting to activating the MCM complex. J. Cell Sci. 2001;114:1447–1454.
- Li J., Zhao W., Akbani R., Liu W., Ju Z., Ling S., Vellano C.P., Roebuck P., Yu Q., Eterovic A.K. Characterization of human cancer cell lines by reverse-phase protein arrays. Cancer Cell. 2017;31:225–239.
- McAlister G.C., Nusinow D.P., Jedrychowski M.P., Wühr M., Huttlin E.L., Erickson B.K., Rad R., Haas W., Gygi S.P. MultiNotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes. Anal. Chem. 2014;86:7150–7158.
- Medico E., Russo M., Picco G., Cancelliere C., Valtorta E., Corti G., Buscarino M., Isella C., Lamba S., Martinoglio B. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat. Commun. 2015;6:7002.
- Mertins P., Mani D.R., Ruggles K.V., Gillette M.A., Clauser K.R., Wang P., Wang X., Qiao J.W., Cao S., Petralia F., NCI CPTAC Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016;534:55–62.
- Millevoi S., Loulergue C., Dettwiler S., Karaa S.Z., Keller W., Antoniou M., Vagner S. An interaction between U2AF 65 and CF I(m) links the splicing and 3′ end processing machineries. EMBO J. 2006;25:4854–4864.
- Narlikar G.J., Sundaramoorthy R., Owen-Hughes T. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell. 2013;154:490–503.
- Ochoa D., Jonikas M., Lawrence R.T., El Debs B., Selkrig J., Typas A., Villén J., Santos S.D., Beltrao P. An atlas of human kinase regulation. Mol. Syst. Biol. 2016;12:888.
- Ohta S., Tatsumi Y., Fujita M., Tsurimoto T., Obuse C. The ORC1 cycle in human cells: II. Dynamic changes in the human ORC complex during the cell cycle. J. Biol. Chem. 2003;278:41535–41540.
- Petryszak R., Keays M., Tang Y.A., Fonseca N.A., Barrera E., Burdett T., Füllgrabe A., Fuentes A.M., Jupp S., Koskinen S. Expression Atlas update--an integrated database of gene and protein expression in humans, animals and plants. Nucleic Acids Res. 2016;44(D1):D746–D752.
- Petsalaki E., Helbig A.O., Gopal A., Pasculescu A., Roth F.P., Pawson T. SELPHI: correlation-based identification of kinase-associated networks from global phospho-proteomics data sets. Nucleic Acids Res. 2015;43(W1):W276–W282.
- Popat S., Hubner R., Houlston R.S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 2005;23:609–618.
- Prasanth S.G., Prasanth K.V., Stillman B. Orc6 involved in DNA replication, chromosome segregation, and cytokinesis. Science. 2002;297:1026–1031.
- Robinson J.T., Thorvaldsdóttir H., Winckler W., Guttman M., Lander E.S., Getz G., Mesirov J.P. Integrative genomics viewer. Nat. Biotechnol. 2011;29:24–26.
- Ruepp A., Waegele B., Lechner M., Brauner B., Dunger-Kaltenbach I., Fobo G., Frishman G., Montrone C., Mewes H.W. CORUM: the comprehensive resource of mammalian protein complexes--2009. Nucleic Acids Res. 2010;38:D497–D501.
- Sadanandam A., Lyssiotis C.A., Homicsko K., Collisson E.A., Gibb W.J., Wullschleger S., Ostos L.C.G., Lannon W.A., Grotzinger C., Del Rio M. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 2013;19:619–625.
- Stefely J.A., Kwiecien N.W., Freiberger E.C., Richards A.L., Jochem A., Rush M.J.P., Ulbrich A., Robinson K.P., Hutchins P.D., Veling M.T. Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling. Nat. Biotechnol. 2016;34:1191–1197.
- Szklarczyk D., Franceschini A., Wyder S., Forslund K., Heller D., Huerta-Cepas J., Simonovic M., Roth A., Santos A., Tsafou K.P. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–D452.
- Thompson M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie. 2009;91:309–319.
- Wang J., Ma Z., Carr S.A., Mertins P., Zhang H., Zhang Z., Chan D.W., Ellis M.J., Townsend R.R., Smith R.D. Proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Mol. Cell. Proteomics. 2017;16:121–134.
- Wickramasinghe V.O., Laskey R.A. Control of mammalian gene expression by selective mRNA export. Nat. Rev. Mol. Cell Biol. 2015;16:431–442.
- Wilkerson M.D., Hayes D.N. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26:1572–1573.
- Zhang B., Wang J., Wang X., Zhu J., Liu Q., Shi Z., Chambers M.C., Zimmerman L.J., Shaddox K.F., Kim S., NCI CPTAC Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513:382–387.
- Zhang H., Liu T., Zhang Z., Payne S.H., Zhang B., McDermott J.E., Zhou J.Y., Petyuk V.A., Chen L., Ray D., CPTAC investigators Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cell. 2016;166:755–765.
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