Molecular Oncology and Ovarian Pathologies
The main aim of the research performed by our team is to provide insights into ovarian function through molecular genetics. A historical subject of the group has been the analysis of the Blepharophimosis syndrome, involving craniofacial defects and premature ovarian insufficiency (POI), due to alterations of the transcription factor FOXL2. Through the years, we have contributed to a better understanding of its molecular function, pathogenic mechanisms and uncovered many targets and partners. FOXL2 provides an excellent model to study combinatorial transcriptional regulation, because it modulates a series of seemingly unrelated processes (i.e., cholesterol and steroid metabolism, apoptosis, cell cycle, free radical detoxification, etc). This wide array of regulated processes raises the question of how FOXL2 achieves a specific target regulation. Thus, we are using it as a model to explore the basis of specific target recognition by a transcription factor and the influence of the partners and post-translational modifications on this process using up-to-date genomics.
FOXL2 has opened an avenue of research regarding ovarian granulosa cell tumors (GCTs), which represent up to 8% of all ovarian cancers. Two distinct subtypes of GCTs have been described: the juvenile and the adult forms. The adult type most often appears during the perimenopausal period and is characterized by a late recurrence (up to 40 years after treatment of the primary tumor). The juvenile forms (JGCTs) tend to occur in the prepubertal period. A highly recurrent somatic mutation of FOXL2, leading to the amino acid substitution p.C134W has been detected in more than 97% of AGCTs, suggesting it is a key element in their formation. We are actively studying the pathogenic mechanisms of this mutation using CRISPR-Cas9-engineered cell lines and genomics.
The molecular bases of JGCTs are less well understood. We have recently found in-frame tandem duplications in the oncogene encoding AKT1 that affect the pleckstrin-homology domain (PHD) of the protein in more than 60% of JGCTs. The effects of such mutations are currently being studied with cellular and a series of Drosophila models.
Finally, we are taking advantage of the power of current genomic technology and we are performing exome sequencing in familial and isolated cases of female infertility due to POI to discover novel genes implicated in this disorder. The function of the latter is being or will be studied using molecular approaches and animal models.
Sources de financement autres que la dotation récurrente :
1) ANR (National Agency for Research) : SEXMAINTAIN : Role of TRIM28 in the maintenance of ovarian identity and primary sex-determination
2) Equipe labelisée FRM (Medical Research Foundation) : Genetics and Genomics of premature ovarian insufficiency: a window to understand ovarian function.
3) GEFLUC (Groupement des Entreprises Françaises dans la Lutte contre le Cancer): Molecular and cellular effects of somatic in-frame duplications within the AKT1 oncogene in ovarian juvenile granulosa cell tumors.
4) Agence Nationale de la Biomédecine. Identification de nouveaux gènes impliqués dans la fertilité féminine
Sélection of publications
Fouquet B, Pawlikowska P, Caburet S, Guigon C, Mäkinen M, Tanner L, Hietala M, Urbanska K, Bellutti L, Legois B, Bessieres B, Gougeon A, Benachi A, Livera G, Rosselli F, Veitia RA*, Misrahi M*. *co-senior authors. A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian Insufficiency.
Elife. 2017 Dec 12;6. pii: e30490.
Veitia RA, Govindaraju DR, Bottani S, Birchler JA. Aging: Somatic Mutations, Epigenetic Drift and Gene Dosage Imbalance.
Trends Cell Biol. 2017 Apr;27(4):299-310.
Bottani S, Veitia RA. Hill function-based models of transcriptional switches: impact of specific, nonspecific, functional and nonfunctional binding.
Biol Rev Camb Philos Soc. 2017 May;92(2):953-963.
Auguste A, Bessière L, Todeschini AL, Caburet S, Sarnacki S, Prat J, D'angelo E, De La Grange P, Ariste O, Lemoine F, Legois B, Sultan C, Zider A, Galmiche L, Kalfa N, Veitia RA. Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads.
Hum Mol Genet. 2015 Dec 1;24(23):6687-98.
Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, García-Tuñón I, Fellous M, Pendás AM, Veitia RA, Vilain E. Mutant Cohesin in Premature Ovarian Failure.
The New England Journal of Medecine, 2014; ; 370:943-949.
Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA. The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells.
Elife. 2014 Nov 4;3.
Gibson TJ, Seiler M, Veitia RA. The transience of transient overexpression.
Nat Methods. 2013 Aug;10(8):715-21.