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Discovery of new biomarkers

Published on 21 August 2020
Discovery and assessment of bladder cancer biomarkers (DECanBio)
Coordinator: Jérôme Garin (EDyP)
EDyP correspondent: Christophe Masselon (EDyP)
Funded by: Projet Européen FP7 (HEALTH)

The DECanBio project aims to develop and apply an innovative strategy for the discovery and validation of protein biomarkers. Our approach is based on the use of novel advanced mass spectrometry methods for quantitative analysis of proteins. The pilot problem chosen was the early detection of bladder cancer based on proteins present in urine. The DECanBio consortium groups together the efforts of seven partners: two clinical research institutes, a public health establishment, three proteomics laboratories, and two industrial partners. The partnership extends across five European countries. The project is divided into three phases: discovery of candidate biomarkers by multiple methodological approaches (in particular the AMT method) in a large multicentre cohort; qualification of candidate biomarkers by a targeted proteomics method (SRM); verification of the qualified candidates on a second, larger cohort, including patients with diseases which could be confused with bladder cancer.

Publications:
Makridakis M and Vlahou A
Secretome proteomics for discovery of cancer biomarkers.
Journal of Proteomics, 2010, 73(12): 2291-2305

Selevsek N, Matondo M, Sanchez Carbayo M, Aebersold R and Domon B
Systematic quantification of peptides/proteins in urine using selected reaction monitoring.
Proteomics, 2011, 11(6): 1135-1147

Court M, Selevsek N, Matondo M, Allory Y, Garin J, Masselon CD and Domon B
Towards a standardized urine proteome analysis methodology.
Proteomics, 2011, 11(6): 1160-1171
Development of an integrated identification approach for markers involved in lymphoma pathogenesis (CT_LYMPH)
Coordinator:
Saadi Khochbin et Mary Callanan (Institut Albert Bonniot, Grenoble)
EDyP correspondent:
Anouk Emadali
Funded by:
INCA/DHOS - Recherche translationnelle

This project is developed in close collaboration with two teams at the Institut Albert Bonniot, Grenoble: "Epigenetics and Cellular Signalling" (Saadi Khochbin) and "Oncogenic Pathways in Malignant Blood Diseases" (Mary Callanan).

In most cancers, cellular transformation to malignant cells results in genetic or epigenetic alterations. These can lead to ectopic expression of specific genes in a particular tissue or cell type. For example, some genes which are normally expressed exclusively in the testes were found to be sporadically de-repressed in some somatic cancers. These gene products were named CT, for Cancer Testis. For a given cancer, these ectopic expressions are therefore good candidate biomarkers (Wang et al., 2011). A new strategy to identify markers of cancer was developed as part of this project based on the CT concept.

In this novel approach, comparative proteomics between healthy and cancer samples is not necessary, rather we simply perform proteomics analysis on disease samples (in this case lymphoma cell lines). We then use transcriptomics data to
1) identify candidate markers with an "out of context" expression pattern and
2) validate their potential using clinical data (aggressivity, disease stage and progression, survival) available for some transcriptomics studies in the public domain.

This project allowed us to identify several potential markers. We selected one of these candidates presenting an "out of context" expression profile for the second part of this project. This protein was confirmed to be over expressed in aggressive lymphoid cancers, it was also found to be associated with poor prognosis in these diseases. Using an interference RNA approach to inactivate expression of this protein in cellulo and in vivo (xenotransplantation model), we were able to validate its role in tumour development and to show that it is also involved in the response to anti-CD20 immunotherapy. Anti-CD20 immunotherapy is currently the reference treatment for lymphoma; this diagnostic and prognostic marker could therefore represent a therapeutic target for better clinical management of this type of cancer. These results were valorised through a European patent, the corresponding article has been submitted.

This project was one of the first to use the SILAC approach for relative protein quantification in our laboratory (Emadali et al., 2009), and to use MaxQuant (developed by Matthias Mann's group at the Max Planck Institute, Munich). This was part of a study of the response of lymphoma lines to inhibitors of histone deacetylases.



Publications:
Wang J, Emadali A, Le Bescont A, Callanan M, Rousseaux S and Khochbin S
Induced malignant genome reprogramming in somatic cells by testis-specific factors.
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2011, 1809(4-6): 221-225

Emadali A and Gallagher-Gambarelli M
Quantitative proteomics by SILAC: Practicalities and perspectives for an evolving approach.
Medecine Sciences (Paris), 2009, 25(10): 835-842

Patent:
European patent: EP 11196053.0