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© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Lab-on-chip for cancer diagnosis Pierre GRANGEAT, IEEE Senior Member CEA-LETI, MINATEC, Département microTechnologies pour la Biologie et la Santé CEA/GRENOBLE, 17, rue des Martyrs, GRENOBLE cedex 9, France Tél: DTBS/STD/ Nano-Bio-Sensing Summer School EPFL, Lausanne, Switzerland, June 29th – July 3rd, 2009

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ With the contribution of Florence RICOUL(1), Nicolas SARRUT(1), Laurent GERFAULT(1), Caroline PAULUS(1), Grégory STRUBEL(1), Myriam CUBIZOLLES (1), Emeline MERY (1), Lucie BAUJARD LAMOTTE (1), Olivier CONSTANTIN (1), Jean-François GIOVANNELLI(2), Virginie BRUN(3), Alain DUPUIS(3), Jérôme GARIN(3), Jürgen SCHNEKENBURGER(4), Manolis TSIKNAKIS(5), Dimitris KAFETZOPOULOS(5), Manuel PEREZ(6), Blanca JORDAN(6) and the LOCCANDIA and CAPSI project teams. (1) CEA-LETI, MINATEC, Département microTechnologies pour la Biologie et la Santé CEA/GRENOBLE, 17, rue des Martyrs, Grenoble cedex 9, France (2) Université de Bordeaux, IMS/LAPS, Equipe Signal et Image, 351 Cours de la Libération, F-33405, Talence cedex, France. (3) CEA, DSV, iRTSV / INSERM U880 Etude de la Dynamique des Protéomes, CEA/GRENOBLE, 17, rue des Martyrs, Grenoble cedex 9, France (4) Westfaelische Wilhelms-Universitaet Muenster, Department of Medecine B Gastrointestinal Molecular Cell Biology, Domagkstrasse 3A, Münster, D-48149, Germany (5) FORTH, Foundation for Research and Technology – IMBB & ICS, Vassilika Vouton, Heraklion 71110, Greece (6) ATOS Research and Innovation, Biotechnology and Health Unit,C/ Albarracin 25, Madrid 28035, Spain

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ FULL TITLE: Lab-On-Chip based protein profiling for CANcer DIAgnosis Project granted by the European Commission: Reference: FP6/2005/IST/5/ Call: Priority Micro/nano based sub-system Web site: WWU SIB, GeneBIO CEA-Leti, CEA-Ibitec ATOS ORIGIN FORTH List of partners : Atos Origin sae, Spain – ATOS Commissariat à l’Energie Atomique, France – CEA- LETI, CEA-IBITEC Foundation for Research and Technology, Greece – FORTH University of Münster, Germany – WWU Swiss Institute of Bioinformatics, Switzerland – SIB Geneva Bioinformatics, Switzerland - GeneBIO LOCCANDIA Project Reference: Jordan B. et al. (2008), " LOCCANDIA: Lab-on-Chip Based Protein Profiling for Cancer Diagnosis ", 5th pHealth Workshop on wearable micro and nano systems for personalised health "from research into practice", Valencia, Spain.

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ ATOS: Blanca Jordán, José F. Esteban, Manuel Perez CEA-LETI: Pierre Grangeat, Laurent Gerfault, Caroline Paulus, Grégory Strubel, Florence Ricoul, Myriam Cubizolles, Emeline Mery, Lucie Baujard Lamotte, Caroline Fontelaye, Guillaume Nonglaton, Françoise Vinet, Nicolas Sarrut, Olivier Constantin CEA-LEMM: François FENAILLE, Cédric MESMIN, Eric EZAN FORTH: Dimitris Kafetzopoulus, Manolis Tsiknakis, Sophie Kaforou, Hara Roumpaki, George Potamias, Haris Kondylakis, Manolis Kalaitz, Vangelis Kritsotakis WWU: Jürgen Schnekenburger, Verena Schick, Jasna Peter- Katalinic, Laura Bindila, Daniela Hahn, Rainer Ossig SIB: Frédérique Lisacek GeneBIO: Pierre-Alain Binz LOCCANDIA Project teams

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ CAPSI Project Full title: – chaîne d’analyse protéomique multifactorielle haute sensibilité à composants intégrés – high sensitivity multifactorial proteomic analytical chain based on integrated components Project granted by the Commissariat à l’Energie Atomique (CEA)within the program “Technology for healthcare” CAPSI project teams: – CEA-LETI: Pierre Grangeat, Laurent Gerfault, Caroline Paulus, Grégory Strubel, Florence Ricoul, Myriam Cubizolles, Emeline Mery, Lucie Baujard Lamotte, Agnès Fonverne, Guillaume Nonglaton, Caroline Fontelaye, Françoise Vinet, Nicolas Sarrut, Olivier Constantin – CEA-iRTSV-EDyP: Jérôme Garin, Alain Dupuis, Virginie Brun, Dorothée Lebert, Mathieu Trauchessec, Annie Adrait, Christophe Bruley, Véronique Dupierris

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The Digital Patient The Digital Patient for eHealth : - The combination of complementary multimodal representations The bio-profiles = a multiparametric description - morphological profiles - molecular profiles - physiological profiles Imaging systems = localisation of the information Healthcare objectives = early diagnosis, personnalized healthcare, home healthcare monitoring

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The molecular profiles a disease is characterized by a molecular signature (cancer, infectious disease, immunological disease,…) multiparametric approach : a set of genes, proteins, therapeutical molecules, functional relationships Need to recognize signatures on molecular profiles molecular profiles : a fundamental information for personnalized healthcare, risk factor analysis, early detection, therapeutical planning and follow- up, drug development, system biology.

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The Nano-Bio-Info-Cogno (NBIC) Convergence Blood plasma sample Blood sample preparation Lab-on-Chip & mass spectrometry Information technology Selected protein mixture Peptides spectrogram Diagnostic information BIO Material flowInformation flow NANO INFO Patient Doctor 6 The chain for high sensitivity lab-on-chip based proteomic analysis

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Lab-on-chip for in-vitro molecular diagnosis General trend towards micro-nano bio systems (MNBS) for in vitro diagnosis Microfluidics is broadly recognized as a key solution to support molecular diagnostic and point-of-care devices. Nanotechnologies for: – nanoparticles for in-vitro molecular interaction – surface functionalization – fluid handling – transduction Key requirement: to perform better, faster, cheaper and smaller analysis, but still reproducible, sensitive and reliable

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Conference highlight Clinical proteomics Micro-nano technologies for microfluidic analysis coupled with mass spectrometry Information processing Conclusion

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Metabolic pathway from DNA to protein Intracellular genetic information flow from DNA to RNA (transcription) and from RNA to protein (translation) Source: Alberts, Johnson et al.(2004), Biologie moléculaire de la cellule, Médecines-Sciences, Flammarion Transcription Translation DNA Protein RNA

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Splicing between primary RNA and messager RNA Alternative splicing produces different isoforms Ref: Alberts, Johnson et al, Biologie moléculaire de la cellule, Médecines Sciences Flammarion Ref: Stryer, Berg, Tymoczko, Biochimie, Médecines Sciences Flammarion RNA splicing and isoforms

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Epitope and antibody recognition An antibody does recognize a specific group of amino-acids at the surface of the protein called epitope Antibody recognition cannot differentiate between isoforms which include the same epitope Epitope Ref. schéma: Stryer, Berg, Tymoczko, Biochimie, Médecines Sciences Flammarion Protein Antibody

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Systems biology Source: Aebersold R & Mann M. (2003), Nature, 422, p Proteins are key nodes in the biomolecular network studied by systems biology

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The 2 main diagnostic modes in proteomic 1.First mode: The cell = a protein sensor – The protein get attach to the membrane – The protein get inside the cell Diagnostic principle: a marker (a label) is attached to the protein and we image the cells which have captured the labelled proteins. The technique is defined by the type of marker which is used: – Nuclear imaging (radioactive marker) – Luminescent or fluorescent imaging (luminescent or fluorescent marker) – Nuclear Magnetic Resonance imaging (magnetic marker) Cell Protein

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The 2 main diagnostic modes in proteomic 2.Second mode: The cell = a protein emitter Diagnostic principle based on: – the proteins – The modification of protein structure Translational modifications Post-translational modifications The information can be: – direct: the target is the emitted protein – indirect: the protein is cleaving a circulating protein that is the target Cell protein Cell protein interaction Direct measure Indirect measure

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Proteomic, cancer, and molecular profiling Proteomic: to describe the molecular signals and the activation states in the cell and its nearby environment Signal network perturbation induces the fact that the cells do not control anymore their growth, leading to the development of tumoral lesions ( unbalanced between survival proteins and apoptosis) Each cancer patient has his own pathologic molecular profile. Multiparametric approach: to combine several markers in order to improve the sensitivity and the specificity. Cancer mechanisms linked to proteins: – Tumor cells produce aberrant proteins – Tumor cells produce cleavage products which degrades proteins within the blood – Non-tumor cells respond to signals emitted remotely by tumoral cells

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Predisposition Screening Diagnostic, grading, typology Treatment Follow-up, monitoring Taking care of patient proteomic profile Care cycle of a disease like cancer

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ The challenges of protein analysis in plasma High sensitivity – Our objective: 1 to 1000 ng/ml Very large dynamic ratio in protein concentration: – Total protein content in plasma: ~100 mg/ml – 1 ng/ml corresponds to a ratio of 1 to 10 8 between the targeted proteins and the total protein content A large protein content: – About 3000 proteins identified in the plasma by the HPPP

© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Dynamic range of protein concentration in plasma Reference intervals for 70 protein analytes in plasma. Abundance is plotted on a log scale spanning 12 orders of magnitude. Source: Anderson N.L., Anderson N.G. (2003), Molecular & Cellular Proteomics, Vol 2.1, p. 50.

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© CEA Tous droits réservés. Toute reproduction totale ou partielle sur quelque support que ce soit ou utilisation du contenu de ce document est interdite sans l’autorisation écrite préalable du CEA All rights reserved. Any reproduction in whole or in part on any medium or use of the information contained herein is prohibited without the prior written consent of CEA Funded by EC contract FP Lab-on-chip for cancer diagnosis P. Grangeat et al. DTBS/STD/ Micro-nano technology objective: lab-on-chip Point of care : Full system from blood plasma sample to diagnostic information Lab-on-Chip : Miniaturized integrated components to increase sensitivity (nano-LC, nano-ESI) and throughput

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