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MYCN, proliferative heterogeneity and treatment response in neuroblastoma

Ryl, Tatsiana

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Abstract

The amplification of the MYCN oncogene, occurring in 20% of neuroblastomas, a tumor of early childhood, is associated with drug-resistant relapse and poor prognosis. High MYCN expression has paradoxical effects in most cells: it promotes cell cycle progression and sensitizes to cell death. This work aims to characterize, at population and single-cell level, the mechanisms through which amplified MYCN allows tumor regrowth after chemotherapy in neuroblastoma. In MYCN-regulatable neuroblastoma cell line models, MYCN shortens the lengths of cell cycle phases, preferentially in G1, and increases the proportion of cycling cells under exponential growth. Upon DNA-damage induced by the chemotherapeutic agent, doxorubicin (DOX), MYCN delays activation of cell cycle checkpoints and boosts the proportion of transiting cells. During and after chemotherapy MYCN favors cell death and suppresses cellular senescence, shifting p53 downstream effects from cell cycle arrest to apoptosis. However, MYCN also drives clonal regrowth of a small fraction of surviving resister cells after DNA-damage. These resister cells exhibit nearly identical molecular and phenotypic profiles as cells before treatment. Live-cell imaging reveals that resister cells arise exclusively from the G1-phase-arrested subpopulation and rapidly repair DNA-damage-induced double-strand breaks (DSBs). The suppression of DNA repair via ATM inhibition during chemotherapy results in reduction of G1 phase arrest and prevents DNA DSB repair, completely eradicating resister cells. Taken together, these data show that non-genetic tumor heterogeneity and a key oncogenic lesion, MYCN, synergize to resume cellular proliferation after DNA damage and probably cause chemotherapy resistance. This work indicates that improved first-line therapies could specifically target resister cells and help avoid cellular regrowth.

Item Type: Dissertation
Supervisor: Höfer, Prof. Dr. Thomas
Date of thesis defense: 21 March 2016
Date Deposited: 01 Jun 2016 06:49
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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