Research Research

OncoProteomics Laboratory

For more information on our proteomics research go to  www.oncoproteomics.nl

OncoProteomics for biomarker discovery and validation at the OncoProteomics Laboratory

Translational research: mission of the OPL

The mission of the OPL is to develop and implement innovative proteomics technologies and data analysis methods to improve diagnostics and treatment of cancer.

Introduction to the research 

The OncoProteomics Laboratory (OPL) has been founded in April 2006 together with the establishment of the cancer research building of the VUmc-Cancer Center Amsterdam (CCA) and is housed at the department of Medical Oncology. The OPL was created to provide a state-of-the-art proteomics infrastructure and knowledge center for CCA/V-ICI researchers. 
Proteomics creates a link between genomic information and biological function through large-scale analysis of protein expression, protein modification and protein-protein interactions. Recent advances in key proteomics tools such as mass spectrometry (MS) and (bio)informatics provide tremendous opportunities for biomarker-related clinical applications. Current MS platforms allow for the detection, quantitation and identification of hundreds to thousands of peptides and proteins in complex biological and clinical samples.

Proteomics applications in cancer include:

  • Discovery of novel cancer (subtype) and treatment (outcome)-related signatures and candidate protein biomarkers
  • Insight into oncogenesis mechanisms
  • Discovery of novel protein targets for therapeutic intervention.

Group photo OncoProteomics Laboratory, sept. 2009. From left to right, top: Jaco C. Knol, Inge de Reus, Connie R. Jiménez, Tieneke Schaaii-Visser, Silvina Fratantoni, Huub Kant. Bottom: Sander Piersma, Marc Warmoes, Mehrdad Lavaei, Thang V. Pham

Some recent research highlights and strategies

Robust mass spectrometry-based strategies for biomarker discovery in tumor tissue and biofluids (serum, cerebrospinal fluid, urine) have been set up and validated. In addition, cancer cell conditioned media and tumor secretomes hold great promise for discovery of candidate serum biomarkers and are a spear-point of our biomarker research. The samples are profiled using two complementary platforms (see figure) for the discovery of diagnostic, predictive and drug response peptide patterns and biomarkers:

  1. An automated magnetic bead-based biofluid peptide capture method coupled to high-throughput MALDI-TOF/TOF mass spectrometry and
  2. Nano-liquid chromatography on-line coupled to LTQ-FT mass spectrometry for in-depth profiling of sub-fractionated samples.

In the three years since the foundation of the OncoProteomics Laboratory, we have moved from initial studies for proteomics method exploration and validation to some successful cancer applications, both in model systems and human material. For example, high-throughput (HTP) body fluid peptide mass profiling in conjunction for pattern diagnostics, applied to non-small cell lung cancer sera of a phase I study was able to predict tumor response and progression-free survival with high accuracy and sensitivity. Moreover, in-depth proteomics of sub-nuclear and secreted fractions of colorectal cancer tissues have yielded promising candidate biomarkers with potential for early detection and treatment response stratification, for which a patent was filed.

Recent publications 

2014

van der Mijn JC, Sol N, Mellema W, Jiménez CR, Piersma SR, Dekker H, Schutte LM, Smit EF, Broxterman HJ, Skog J, Tannous BA, WürdingerT, Verheul HM. Analysis of AKT and ERK1/2 protein kinases in extracellular vesicles isolated from blood of patients with cancer. J Extracell Vesicles 2014; 3: 25657. doi: 10.3402/jev.v3.25657. eCollection 2014.

Emmink BL, Laoukili J, Kipp AP, Koster J, Govaert KM, Fatrai S, Verheem A, Steller EJ, Brigelius-Flohe R, Jiménez CR, Borel Rinkes IH, Kranenburg O. GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer. Cancer Res 2014; 74: 6717-6730.

Labots M, Schütte LM, van der Mijn JC, Pham TV, Jiménez CR, Verheul HM. Mass spectrometry-based serum and plasma peptidome profiling for prediction of treatment outcome in patients with solid malignancies. The Oncologist 2014; 19: 1028-1039.

Rajcevic U, Knol JC, Piersma S, Bougnaud S, Fack F, Sundlisaeter E, Søndenaa K, Myklebust R, Pham TV, Niclou SP, Jiménez CR. Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture. Proteome Sci 2014; 12: 39. doi: 10.1186/1477-5956-12-39.

Hassan C, Kester MG, Oudgenoeg G, de Ru AH, Janssen GM, Drijfhout JW, Spaapen RM, Jiménez CR, Heemskerk MH, Falkenburg JH, van Veelen PA. Accurate quantitation of MHC-bound peptides by application of isotopically labeled peptide MHC complexes. J Proteomics 2014; 109C: 240-244.

Daleke-Schermerhorn MH, Felix T, Soprova Z, Ten Hagen-Jongman CM, Vikström D, Majlessi L, Beskers J, Follmann F, de Punder K, van der Wel NN, Baumgarten T, Pham TV, Piersma SR, Jiménez CR, van Ulsen P, de Gier JW, Leclerc C, Jong WS, Luirink J. Decoration of outer membane vesicles with multiple antigens using an autotransporter approach.Appl Eviron Microbiol 2014; 80: 5854-5865.

Senol O, Schaaij-Visser TB, Erkan EP, Dorfer C, Lewandrowski G, Pham TV, Piersma SR, Peerdeman SM, Ströbel T, Tannous B, Saydam N, Slavc I, Knosp E, Jiménez CR, Saydam O. miR-200a-mediated suppression of non-muscle heavy chain IIb inhibits meningioma cell migration and tumor growth in vivo. Oncogene 2014; doi: 10.1038/onc.2014.120.

Jiménez CR, Verheul HM. Mass spectrometry-based proteomics: from cancer biology to protein biomarkers, drug targets, and clinical applications. Am Soc Clin Oncol Educ Book 2014; 34: e504-510. doi: 10.14694/EdBook_AM.2014.34.e504.

Chiasserini D, van Weering JRT, Piersma SR, Pham TV, Malekzadeh A, Teunissen CE, de Wit H, Jiménez CR. Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. J Proteomics 2014; 106C: 191- 204.

Knol JC, de Wit M, Albrethsen J, Piersma S, Pham TV, Mongera S, Carvalho B, Fijneman RJ, Meijer GA, Jiménez CR. Proteomics of differential extraction fractions enriched for chromatin-binding proteins from colon adenoma and carcinoma tissues. Biochim Biophys Acta 2014; 1844: 1034-1043.

de Wit M, Kant H, Piersma SR, Pham T, Mongera S, van Berkel MP, Boven E, Pontén F, Meijer GA, Jiménez CR, Fijneman RJ. Colorectal cancer candidate biomarkers identified by tissue secretome proteome profiling. J Proteomics 2014; 99: 26-39.

Lam SW, Jiménez CR, Boven E. Breast cancer classification by proteomic technologies: Current state of knowledge. Cancer Treat Rev 2014; 40: 129-138.

2013

Bijnsdorp IV, Geldof AA, Lavaei M, Piersma SR, van Moorselaar RJ, Jiménez CR. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J Extracell Vesicles  2013; 2. doi: 10.3402/jev.v2i0.22097.

Posthuma-De Boer J, Piersma SR, Pham TV, van Egmond PW, Knol JC, Cleton-Jansen AM, van Geer MA, van Beusechem VW, Kaspers GJL, van Royen BJ, Jiménez CR, Helder MN. Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. Br J Cancer 2013; 109: 2142-2154.

Snoeren N, Emmink BL, Koerkamp MJ, van Hooff SR, Goos JA, van Houdt WJ, de Wit M, Prins AM, Piersma SR, Pham TV, Belt EJ, Bril H, Stockmann HB, Meijer GA, van Hillegersberg R, Holstege FC, Jiménez CR, Fijneman RJ, Kranenburg OW, Rinkes IH. Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer. Br J Cancer 2013; 109: 1636-1647.

Kooij V, Zhang P, Piersma SR, Sequeira V, Boontje NM, Wijnker PJ, Jiménez CR, Jaquet KE, dos Remedios C, Murphy AM, Van Eyk JE, van der Velden J, Stienen GJ. PKCa-specific phosphorylation of the troponin complex in human myocardium: a functional and proteomics analysis. Plos One 2013; 8(10):e74847. doi: 10.1371/journal.pone.0074847.

Petersen K, Rajcevic U, Abdul Rahim SA, Jonassen I, Kalland KH, Jiménez CR, Bjerkvig R, Niclou SP. Gene set based integrated data analysis reveals phenotypic differences in a brain cancer model.  PLos One  2013; 8(7):e68288. doi: 10.1371/journal.pone.0068288.

Emmink BL, Verheem A, Van Houdt WJ, Steller EJ, Govaert KM, Pham TV, Piersma SR, Borel Rinkes IH, Jiménez CR, Kranenburg O. The secretome of colon cancer stem cells contains drug-metabolizing enzymes. J Proteomics 2013; 91C: 84-96.

De Vries-van Leeuwen IJ, da Costa Pereira D, Flach KD, Piersma SR, Haase C, Bier D, Yalcin Z, Michalides R, Feenstra KA, Jiménez CR, de Greef TF, Brunsveld L, Ottmann C, Zwart W, de Boer AH. Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface. Proc Natl acad Sci USA 2013; 110: 8894-8899.

Piersma SR, Warmoes MO, de Wit M, de Reus I, Knol JC, Jiménez CR. Whole gel processing procedure for GeLC-MS/MS based proteomics. Proteome Sci 2013; 11: 17. Doi: 10.1186/1477-5956-11-17.

Warmoes M, Jaspers JE, Xu G, Sampadi BK, Pham TV, Knol JC, Piersma SR, Boven E, Jonkers J, Rottenberg S, Jiménez CR. Proteomics of genetically engineered mouse mammary tumors identifies fatty acid metabolism members as predictive markers for cisplatin resistance. Mol Cell Proteomics 2013; 12: 1319-1334.

Schaaij-Visser TB, Wit MD, Lam SW, Jiménez CR. The cancer secretome, current status and opportunities in the lung, breast and colorectal cancer context. Biochim Biophys Acta 2013; Jan 30. pii: S1570-9639(13)00040-X.

Albrethsen J, Agner J, Piersma SR, Hojrup P, Pham TV, Weldingh K, Jiménez CR, Andersen P, Rosenkrands I. Proteomic profiling of the Mycobacterium tuberculosis identifies nutrient starvation responsive toxin-antitoxin systems. Mol Cell Proteomics 2013; 12: 1180-1191.

de Wit M, Fijneman RJ, Verheul HM, Meijer GA, Jiménez CR. Proteomics in colorectal cancer translational research: Biomarker discovery for clinical applications. Clin Biochem 2013; 46: 466-479.

2012

Bögels M, Braster R, Nijland PG, Gül N, van de Luijtgaarden W, Fijneman RJ, Meijer GA, Jiménez CR, Beelen RH, van Egmond M. Carcinoma origin dictates differential skewing of monocyte function. Oncoimmunology 2012; 1: 798-809.

Pham TV, Jiménez  CR. An accurate paired sample test for count data. Bioinformatics 2012; 28: i596-i602.

Houben EN, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, Ottenhoff TH, Luirink J, Bitter W. Composition of the type VII secretion system membrane complex. Mol Microbiol 2012; 86: 472-484.

Daleke MH, van der Woude AD, Parret AH, Ummels R, de Groot AM, Watson D, Piersma SR, Jiménez CR, Luirink J, Bitter W, Houben EN. Specific chaperones for the type VII protein secretion pathway. J Biol Chem 2012; 287: 31939-31947.

Kranenburg O, Emmink BL, Knol J, van Houdt WJ, Rinkes IH,Jiménez CR. Proteomics in studying cancer stem cell biology. Expert Rev Proteomics 2012; 9: 325-336.

Pham TV, Piersma SR, Oudgenoeg G, Jiménez CR. Label-free mass spectrometry-based proteomics for biomarker discovery and validation. Expert Rev Mol Diagn 2012;12: 343-359.

Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP,  Waisfisz Q, Rottenberg S, Boven E, Jonkers J, Jiménez  CR. Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with diagnostic and prognostic value in human breast cancer.  Mol Cell Proteomics 2012; 11: M111.013334.

Fijneman RJA, de Wit M, Pourghiasian M, Piersma SR, Pham TV, Warmoes MO, Lavaei M, Piso C, Smit F, Delis - van Diemen PM, van Turenhout ST, Terhaar sive Droste JS, Mulder CJJ, Blankenstein MA, Robanus-Maandag EC, Smits R,  Fodde R, van Hinsbergh VWM, Meijer GA, Jiménez  CR. Proximal fluid proteome profiling of mouse colon tumors reveals biomarkers for early diagnosis of human colorectal cancer. Clin Cancer Res 2012; 18: 2613-2624.

van Dijk KD, Berendse HW, Drukarch B, Fratantoni SA, Pham TV, Piersma SR, Huisman E, Brevé JJ, Groenewegen HJ, Jiménez CR, van de Berg WD. The proteome of the locus ceruleus in Parkinson's disease: relevance to pathogenesis. Brain Pathol 2012; 22: 485-498.

de Wit M, Jiménez CR, Carvalho B, Belien JA, Delis-van Diemen PM, Mongera S, Piersma SR, Vikas M, Navani S, Pontén F, Meijer GA, Fijneman RJ. Cell surface proteomics identifies glucose transporter type 1 and prion protein as candidate biomarkers for colorectal adenoma-to-carcinoma progression. Gut 2012; 61: 855-864.

2011

Knol JC, Jiménez CR. Maldi-tof serum profiling using semiautomated serum Peptide capture with magnetic reversed phase (c18) beads. Methods Mol Biol 2011; 790:3-16.

Teunissen CE, Tumani H, Bennett JL, Berven FS, Brundin L, Comabella M, Franciotta D, Federiksen JL, Fleming JO, Furlan R, Hintzen RQ, Hughes SG, Jiménez CR, Johnson MH, Killestein J, Krasulova E, Kuhle J, Magnone MC, Petzold A, Rajda C, Rejdak K, Schmidt HK, van Pesch V, Waubant E, Wolf C, Deisenhammer F, Giovannoni G, Hemmer B. Consensus guidelines for CSF and blood biobanking for CNS biomarker studies. Mult Scler 2011; 2011: 246412. Epub 2011 Jul 18.

Gast MC, Zapatka M, van Tinteren H, Bontenbal M, Span PN, Tjan-Heijnen VC, Knol JC, Jiménez CR, Schellens JH, Beijnen JH. Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer. J Cancer Res Clin Oncol 2011; 137: 1773-1783.

van Houdt WJ, Emmink BL, Pham TV, Piersma SR, Verheem A, Vries R,  Fratantoni SA, Pronk A, Clevers H, Borel Rinkes IHM, Jiménez CR, Kranenburg O. Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target. Mol Cell Proteomics 2011; 10: M111.011353.

Skvortsov S, Jiménez CR, Knol JC, Eichberger P, Schiestl B, Debbage P, Skvortsova I, Lukas P. Radioresistant head and neck squamous cell carcinoma cells: Intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets. Radiother Oncol 2011; 101: 177-182.

Bosch LJ,  Carvalho B, Fijneman RJ, Jiménez CR, Pinedo HM, van Engeland M, Meijer GA. Molecular tests for colorectal cancer screening. Clin Colorectal Cancer 2011; 10:8-23.

Emmink BL, Van Houdt WJ, Vries RG, Hoogwater FJ, Govaert KM, Verheem A, Nijkamp MW, Steller EJ, Jiménez CR, Clevers H, Rinkes IH, Kranenburg O. Differentiated Human Colorectal Cancer Cells Protect Tumor-Initiating Cells from Irinotecan. Gasteroenterology 2011; 141:269-278.

Teunissen C, Koel-Simmelink M, Pham T, Knol J, Khalil M, Trentini A, Killestein J, Nielsen J, Vrenken H, Popescu V, Dijkstra C, Jiménez C. 
Identification of biomarkers for diagnosis and progression of MS by MALDI-TOF mass spectrometry. Mult Scler 2011; 17:838-850.

2010 

Fratantoni SA, Piersma SR, Jiménez CR. Comparison of the performance of two affinity depletion spin filters for quantitative proteomics of CSF: Evaluation of sensitivity and reproducibility of CSF analysis using GeLC-MS/MS and spectral counting. Proteom Clin Appl 2010; 4:613-617.

Altelaar AF, Piersma SR. Cellular imaging using matrix-enhanced and metal-assisted SIMS. Methods Mol Biol 2010; 656:197-208.

Jiménez CR, Knol JC, Meijer GA, Fijneman RJ. Proteomics of colorectal cancer: Overview of discovery studies and identification of commonly identified cancer-associated proteins and candidate CRC serum markers. J Proteomics 2010; 73:1873-1895.

Piersma SR, Labots M, Verheul HM, Jiménez CR. Strategies for kinome profiling in cancer and potential clinical applications: chemical proteomics and array-based methods. Anal. Bioanal. Chem. 2010; 397:3163-3171.

Sani M, Houben EN, Geurtsen J, Pierson J, de Punder K, van Zon M, Wever B, Piersma SR, Jiménez CR, Daffé M, Appelmelk BJ, Bitter W, van der Wel N, Peters PJ. Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PloS Pathog 2010; Mar 5;6(3):e1000794.

Albrethsen J, Knol JC, Piersma S, Pham TV, de Wit M, Mongera S, Carvalho B, Verheul HM, Fijneman RJ, Meijer GA, Jiménez CR. Sub-nuclear proteomics in colorectal cancer:Identification of proteins enriched in the nuclear matrix fraction and regulation in adenoma to carcinoma progression. Mol Cell Proteomics 2010; 9:988-1005.

Piersma SR, Fiedler U, Span S, Lingnau A, Pham TV, Hoffmann S, Kubbutat MH, Jiménez CR. Workflow comparison for label-free, quantitative secretome proteomics for cancer biomarker discovery: method evaluation, differential Aaalysis, and verification in serum. J. Proteome Res. 2010; 1913-1922.

Pham TV, Piersma SR, Warmoes M, Jiménez CR. On the beta-binomial model for analysis of spectral count data in label-free tandem mass spectrometry-based proteomics. Bioinformatics 2010; 26: 363-369.

Saydam O, Senol O, Schaaij-Visser TB, Pham TV, Piersma SR, Stemmer-Rachamimov AO, Wurdinger T, Peerdeman SM, Jiménez CR. Comparative protein profiling reveals minichromosome maintenance (MCM) proteins as novel potential tumor markers for meningiomas. J Proteome Res 2010; 9: 485-494. 


2009

Chêciñska A., Giaccone G., Rodriguez JA., Kruyt FAE, Jiménez CR. Comparative proteomics analysis of caspase-9-protein complexes in untreated and cytochrome c/ dATP stimulated lysates of NSCLC cells. J Proteomics 2009; 72: 575-585.

Piersma SR, Broxterman HJ, Kapci M., de Haas RR, Hoekman K,  Verheul HMW, Jiménez CR. Proteomics of the TRAP-induced platelet releasate. J Proteomics 2009; 72: 91-109. 
 
Albrethsen J, Knol JC, Jiménez CR. Unravelling the nuclear matrix proteome. J Proteomics 2009; 72: 71-78.

Rajcevic U, Niclou S, Jiménez CR.  Proteomics strategies for target identification and biomarker discovery in cancer. Frontiers Biosci. 2009; 14: 3292-3303.

Gast MC, van Dulken EJ, van Loenen TKG, Kingma-Vegter F, Westerga J, Flohil CC, Knol JC, Jiménez CR,  van Gils CH, Wessels LFA, Schellens JHM, Beijnen JH. Detection of breast cancer by surface-enhanced  laser desorption/ionization time-of-flight mass spectrometry tissue and serum protein profiling. Int J Biol Markers 2009: 24: 130-141.

Voortman J, Pham TV, Knol JC, Giaccone G, Jiménez CR. Prediction of outcome of non-small cell lung cancer patients treated with chemotherapy and bortezomib by time-course MALDI-TOF-MS serum peptide profiling. Proteome Sci. 2009; 7: 34.

Rajcevic U, Petersen K, Knol JC, Loos M, Bougnaud S, Klychnikov O, Li KW, Pham TV, Wang J, Miletic H, Peng Z, Bjerkvig R, Jiménez CR, Niclou SP. iTRAQ based proteomic  profiling reveals increased metabolic activity and cellular crosstalk in angiogenic compared to invasive Glioblastoma phenotype. Mol Cell Proteomics 2009; 8: 2595-2612.

Jiménez CR. Sorting and zooming: subcellular proteomics is booming! (Editorial) J Proteomics 2009; 72: 1-3.

Van Dijk FS, Nesbitt IM,  Zwikstra EH,  Nikkels PGZ,  Smit M, Morsman AC, van Roij MH, Elting M, Cobben  JM, Verbeke JIML, Piersma, SR.,  Jiménez CR,  Fratantoni S,Wijnaendts LCD 7, Shaw  NJ 8,  Hogler W 9, McKeown C, Sistermans EA, Dalton A,  Meijers-Heijboer EJ,  Pals G. PPIB mutations causes lethal/severe osteogenesis imperfecta . Am J Hum Gen. 2009; 85: 521-527.


2008/2007

Pham TV, Van de Wiel M, Jiménez CR. Support Vector machine approach to separate control and breast cancer serum samples. Stat Appl Genet Mol Biol 2008; 7: Article11. 

Jiménez CR, Piersma S, Pham TV. High-throughput and targeted in-depth mass spectrometry-based approaches for biofluid profiling and biomarker discovery. Biomarkers in Medicine 2007; 1: 541-565.

Jiménez CR, Koel-Simmelink M, Pham TV, Van der Voort L, Teunissen CE. Endogeneous peptide profiling of cerebrospinal fluid by MALDI-TOF mass spectrometry: Optimization of magnetic bead-based peptide capture and analysis of preanalytical variables. Prot Clin Appl 2007; 1: 1385-1392. 

Jiménez CR, El Filali Z, Knol JC, Li KW, Hoekman K, Kruyt FAE, Giaccone G, Smit AB. Automated serum peptide profiling using novel magnetic C18 beads off-line coupled to MALDI-TOF mass spectrometry. Prot Clin Appl. 2007; 1: 598-604.