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MYCN modulates the restriction point and ferroptosis in Neuroblastoma

Flórez Amaya, Andrés Felipe

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Neuroblastoma is the most common extracranial solid tumor in childhood. It constitutes an interesting model for tumor progression since the mutation rate is relatively low as compared to other tumors, allowing to investigate specific tumor drivers in a relatively homogeneous genetic background. One of the important drivers of tumor formation in neuroblastoma is the oncogene MYCN. This transcription factor is responsible for the activation of a cascade of genes involved in cell proliferation and metabolism The study of MYCN’s role in these processes is highly relevant because a deep understanding of the regulation could lead to more effective therapies for MYC-driven tumors. In this PhD thesis, an approach was developed to study cell cycle and metabolism on MYCN-driven neuroblastomas. One of the caveats of cell cycle studies is the lack of markers to study cell cycle transition, and the artifacts caused by cell synchronization. By combining the E2F1-d2GFP and Cdt1-degron markers it was possible to identify a G0-like state, which is more prominent upon reduction of MYCN. This state is transient and it was not possible to detect it before in this cell system. The cells under high MYCN expression avoid passing through the G0-like state. This decision happens early in the cell cycle and it is not influenced by p21, contrary to what was found in other studies. Gene expression profiling of sorted cells using the cell cycle markers demonstrated that the transcriptional program of G0-like state caused by MYCN reduction is different from mitogen starvation and contact inhibition, suggesting that the G0-like state might be a spectrum of states with similar phenotypes but distinct expression profiles. As an outlook, the network analysis of the expression data suggests RABL6 as a potential marker of MYCN that controls the commitment to cell cycle by inhibiting p16, however further experiments are required to confirm this finding. From the metabolic perspective, we found that MYCN-high cells are strongly addicted to the amino acid cystine, which serves as a source for the glutathione pathway. Inhibition of enzymes from this pathway shows a dramatic lethal effect exclusively on MYCN-high cells. We found that the mechanism of cell death under cystine starvation in MYCN-amplified cells is ferroptosis, a recently described pathway that involves lipid peroxidation enhanced by iron. To our knowledge, this is the first time that MYCN is associated with ferroptosis which opens an avenue for developing new drugs targeting MYC-driven tumors via induction of ferroptosis.

Item Type: Dissertation
Supervisor: Höfer, Prof. Dr. Thomas
Date of thesis defense: 23 January 2017
Date Deposited: 08 Feb 2017 11:34
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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