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