Team 3

 

 

Metabolism, Integrative genomics & Bioinformatics

 

 

 

The aim of team 3 is to elucidate the role of metabolism, determine biomarkers and therapeutic targets in diseases through an Integrative Genomic approach, in particular in complex metabolic diseases and cancer.

It is structured in 2 tasks:

Genomics of lymphomas and lymphoid pathologies. Several team members work since a long time on transcription profiling of lymphomas, including relapsed Diffuse Large B-Cell Lymphoma (DLBCL). Our objective is to obtain genomic and epigenomic biomarkers od diagnois and prognosis and identify potential therapeutics targets of lymphomas, including DLBCL, Richter Syndrome (RS), Waldenström’s macroglobulinemia (WM) and Marginal Zone Lymphomas (MZL). DLBCL over-expressing Myc are refractory to any treatment. RS, a transformation of Chronic Lymphocytic Leukemia occurs mostly in high-grade lymphoma, for which there is no efficient treatment. We will study genes involved in Non-Homologous End-Joining complex (NHEJ) as markers of diagnosis and prognosis of WM.

Metabolism, Genomics & Cancer. We will study the links between one carbon metabolism and epigenomics modifications of oncogenesis, with two aims. According to promising results, the cellular level of SAM is directly under the influence of one carbon metabolism B12 vitamin and could trigger methionine dependence mechanisms, the cytoplasm targeting of RNA binding proteins and their interactions with non-coding RNAs and the loss of pro-oncogenes promoter methylation, including in meningioma, gastric cancer and leukemia. The first aim will be to identify the interactions between one carbon metabolism and oncogenesis through methylome alterations, post-translational modifications of RBP (with a special interest for HuR) and their consequences on mRNA and non-coding RNAs in cerebral tumors, lung carcinomas and lymphoma/leukemia. The second aim will be to identify the mechanisms and consequences of methionine dependency in cancer stem cells (CSC). We will dissect the metabolic pathways responsible for methionine dependency and we will determine whether methionine restriction eradicates CSC, and prevents tumor growth. We will dissect the underlying transcriptomic and proteomic profiles in human cell lines with « tumor spheres » and different aggressiveness.

 

Selected publications :

  1. Perrot A, Pionneau C, Nadaud S, Davi F, Leblond V, Jacob F, Merle-Béral H, Herbrecht R, Béné MC, Gribben JG, Bahram S, Vallat L. A unique proteomic profile on surface IgM ligation in unmutated chronic lymphocytic leukemia. Blood, 2011, 118, e1-1
  2. Broséus J, Park JH, Carillo S, Hermouet S and Girodon F. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood, 2014, 124, 3964-6
  3. Chen G, Broséus J, Hergalant S, Donnart A, Chevalier C, Bolaños-Jiménez F, Guéant JL, Houlgatte R. Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease. Mol. Nutr. Food Res., 2015, 59, 293-302
  4. Vigouroux C, Casse JM, Battaglia-Hsu SF, Brochin L, Luc A, Paris C, Lacomme S, Gueant JL, Vignaud JM, Gauchotte G. Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma. Lung Cancer, 2015, 89, 189-196
  5. Broséus J, Chen G, Hergalant S, Ramstein G, Mounier N, Guéant JL, Feugier P, Gisselbrecht C, Thieblemont C, Houlgatte R. Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses. Oncotarget, 2016, Jun 2. doi: 10.18632