Entschlüsselung der Telomerase-Abhängigkeit von Neuroblastomzellen
Hämatologie, Onkologie
Kinder- und Jugendmedizin
Zusammenfassung der Projektergebnisse
We previously discovered that activation of telomere maintenance is a discriminating factor that separates high-risk from low-risk neuroblastoma. Our data suggested that telomere maintenance is the key factor driving malignant neuroblastoma growth, whereas its absence enables spontaneous tumour regression. Here, we aimed at evaluating this hypothesis by investigating the mechanistic role of telomerase in various neuroblastoma model systems. To this end, we created a conditional knock-out strategy of the TERT gene in four neuroblastoma cell lines using a CRISPR-Cre system. We identified 10 clones with substantially decreased telomerase activity after induction of TERT knock-out, proving the technical feasibility of the concept. Preliminary results indicate massively reduced cell proliferation in TERT-deficient cells as compared to controls, suggesting that continuous growth of neuroblastoma cells depends on telomerase. In an alternative approach, we generated telomerase-proficient and -deficient MYCN-driven neuroblastoma mouse models. We found that mice of both genotypes developed neuroblastoma within the first few weeks of life, however, that spontaneous regression and digerentiation into benign ganglioneuroma occurred in telomerase-deficient mice, leading to significant improvement of survival. Molecular characterization of murine tumours revealed that induction of cell cycle arrest, digerentiation, senescence, and an inflammatory response occurred in telomerase-deficient, but not telomerase-proficient tumours over the course of disease. Our data, thus, clearly demonstrate that lack of telomere maintenance is the cause of spontaneous regression and digerentiation in neuroblastoma. In an associated project, we also discovered that telomerase is not only a discriminating factor of favourable and unfavourable clinical courses in neuroblastoma, but also in pulmonary carcinoids, suggesting a key role of telomere maintenance in driving human cancer to the fully malignant state. While these findings support the potential value of telomerase as an actionable vulnerability in cancer, we found that currently available telomerase interacting compounds may be limited in their egicacy and/or specificity. In ongoing experiments, we are currently aiming to gain in-depth insights into the molecular processes that are induced by telomerase inactivation, leading to spontaneous regression and digerentiation. Together, our findings may pave the way for developing and evaluating more egicient telomerase inhibitors as anti-cancer drugs in the future.
Projektbezogene Publikationen (Auswahl)
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Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk neuroblastoma models. Cellular Oncology, 45(5), 991-1003.
Fischer-Mertens, Janina; Otte, Felix; Roderwieser, Andrea; Rosswog, Carolina; Kahlert, Yvonne; Werr, Lisa; Hellmann, Anna-Maria; Berding, Maya; Chiu, Bill; Bartenhagen, Christoph & Fischer, Matthias
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TERT Expression and Clinical Outcome in Pulmonary Carcinoids. Journal of Clinical Oncology, 43(2), 214-225.
Werr, Lisa; Bartenhagen, Christoph; Rosswog, Carolina; Cartolano, Maria; Voegele, Catherine; Sexton-Oates, Alexandra; Di Genova, Alex; Ernst, Angela; Kahlert, Yvonne; Hemstedt, Nadine; Höppner, Stefanie; Mansuet Lupo, Audrey; Pelosi, Giuseppe; Brcic, Luka; Papotti, Mauro; George, Julie; Bosco, Graziella; Quaas, Alexander; Tang, Laura H. ... & Girard, Nicolas
