Thèse de doctorat en Biologie Cellulaire et Physiopathologie
Sous la direction de Edith Chevret.
Thèses en préparation à Bordeaux en cotutelle avec l'Université de Porto , dans le cadre de École doctorale Sciences de la vie et de la santé (Bordeaux) , en partenariat avec Merlio (laboratoire) .
Telomere biology of Cutaneous T-cell Lymphomas
Telomere biology plays critical roles in cellular homeostasis. Telomeres are at the borderline between tumor suppression and tumor initiation. Although telomere dysfunction resulting from replicative attrition constrains tumor growth by engaging DNA-damage signaling pathways, it can also promote tumorigenesis. Expression of telomerase enables telomere-length homeostasis and allows tumor cells to escape the antiproliferative barrier posed by short telomeres. Telomere biology is involved in lymphomagenesis of Cutaneos T-cell lymphomas (CTCL), thus we interested in the contributions of hTERT, the catalytical subunit of telomerase, and telomeric repeat-containing RNA (TERRA) to disease initiation and/or progression. We investigated transcriptional and post-transcriptional regulating mechanism of hTERT and we highlighted the major role of alternative mRNA splicing in regulating telomerase non canonical functions in CTCL. We unveiled the participation of TERRA in CTCL lymphomagenesis, which seems to regulate telomere length-dependent telomerase activity. We finally tested the value of lovastatin, a cholesterol-lowering and potential anti-neoplastic agent commonly used in clinic, as an anti-telomerase drug, on CTCL cells. Lovastatin impaired hTERT transcription, decreasing cell viability in vitro and cell dissemination in vivo. Altogether these data provide important insights into telomere biology of CTCL. We contributed to the identification of crucial regulating mechanisms of telomerase as well as we identified new players in CTCL lymphomagenesis, providing new fields of research.