Axis 2 | Regulation of cell division during development and disease

  1. Novel EXOSC10/Rrp6-dependent mechanisms for lncRNA-mediated cancer drug resistance
  2. Identification of new Cancer/Testis genes
  3. Genetic analysis of signaling pathways important for female fertility
Cell division

Novel EXOSC10/Rrp6-dependent mechanisms for lncRNA-mediated cancer drug resistance

Principal Investigators: Michael Primig, Soazik Jamin et Fabrice Petit.

The anti-cancer drug 5-fluorouracil affects DNA replication by targeting TYMS (Thymidylate Synthetase) and lncRNA turnover/processing by inhibiting the conserved exoribonuclease EXOSC10/Rrp6. Drug resistance is a key problem that can be related to the expression or the allele structure of TYMS. However, little is known about cancer-related EXOSC10/Rrp6 alleles, and the question if abnormal EXOSC10/Rrp6 accumulation in cancer cells affects the regulation of lncRNAs, cell proliferation and the response to chemotherapy. To tackle these questions, we study the roles of EXOSC10/Rrp6 in cell division and differentiation in vivo using transgenic mouse models, in vitro using cell lines and in budding yeast. The outcome of our work could reveal EXOSC10 as a prognostic marker and therapeutical target. It may also help optimize 5-FU based therapy in personal medicine by identifying mutations that affect its outcome. 

Relevant publications: PubMed
Funding: Inserm | Université de Rennes 1 | Institut Clinique de la Souris | La Ligue Contre le Cancer | La Région de Bretagne (SAD)

Identification of new Cancer/Testis genes

Principal Investigators: Soazik Jamin, Fabrice Petit and Michael Primig

Personalized medicine is arguably one of the most exciting fields in current biomedical research. One of its sub-fields – personalized immunotherapies – pursues the development of anti-cancer therapies that direct a patient’s immune system toward malign tumors using cancer antigens. Cancer/Testis genes are among the largest groups of promising candidates for cancer therapies based on tumor antigenes. Critically, CT genes can also function as oncogenes. Gametogenesis and somatic tumorigenesis have a number of features in common, including immortalization of primordial germ cells versus transformation of pre-cancerous cells and embryo implantation versus invasion of healthy tissue by cancerous cells. It is therefore important to identify and functionally characterize novel CT genes that are interesting therapeutical targets, since they may help cancer cells acquire the ability to repair DNA damage, invade tissues and suppress apoptosis.   

Relevant publications: PubMed
Funding: Inserm | Inserm Avenir | Université de Rennes 1 | Rennes Metropôle | Association pour la Recherche Contre le Cancer (ARC) | Fondation pour la Recherche Medicale (FRM) | La Ligue Contre le Cancer

Genetic analysis of signaling pathways important for female fertility

Principal investigators: Soazik Jamin and Fabrice Petit

The Anti Müllerian Hormone (AMH) is an essential clinical tool in assisted reproductive medicine and gynecological oncogenesis. The identification of new genes regulated via AMH dependent signaling will help better understand the role of this hormone in the ovary, and may explain in part the etiology of diseases such as polycystic ovary syndrome, which is characterized by increased production of AMH. SMAD proteins are transcription factors involved in TGF-ß, activin, inhibin, BMP and AMH signaling pathways. The Smad4 protein is essential for early embryonic development, particularly at the time of gastrulation. In addition, heterozygous animals have gastric cancers that develop between 4 and 6 months of age. We are interested in Smad4’s role in the male and female reproductive tract.

Relevant publications: PubMed
Funding: ANR JCJC | Inserm | Université de Rennes 1