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Mechanisms of Chromosomal Instability in Glioblastoma

Nayak, Sushma

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Abstract

Chromosomal instability (CIN) is one of the hallmarks of cancer and is found to be a characteristic property of most solid tumors. However, only little is known about the exact mechanisms leading to CIN. On the other hand, CIN is known to drive tumor cell evolution by clonal expansion leading to tumor heterogeneity, providing proliferative advantage, metastatic potential and chemoresistance to tumor cells. Hence, it is of utmost importance to identify causal mutations and delineate the mechanisms involved in CIN development in order to design targeted treatments for such notorious tumors. In this thesis, I analyzed the NCH149 cell line derived from a primary glioblastoma tumor that is highly resistant to chemo- and radiotherapy. Cytogenetic analysis of this cell line revealed extraordinary aneuploidy, clonal heterogeneity and CIN. We could further demonstrate that mitotic chromosome segregation defects and centriole amplification were the causes of CIN in NCH149 cells. With the aim to identify mutated genes that might contribute to the CIN phenotype of NCH149 cells whole exome sequencing was performed. This led to the identification of a novel mutation in the tumor suppressor gene LATS1. Functional characterization of LATS1 protein showed that the identified mutation (p.I615V) interferes with YAP1 binding and prevents phosphorylation of YAP1 causing its nuclear localization. Overexpression of constructs harboring the identified LATS1 mutation influenced the subcellular localization of YAP1. In addition, micronucleus formation and centriole over-duplication was induced by overexpression of mutant LATS1. In addition, we could show that hyperactive YAP1 in NCH149 cells, which is due to mutated LATS1, is an effective drug target to induce cytotoxicity to highly resistant NCH149. Verteporfin, an inhibitor of the transcriptional activity of YAP1, prevents the transcription of downstream targets and by this specifically kills LATS1-mutant NCH149 cells compared to LATS1 wild type NCH82 glioblastoma cells. Therefore, this study demonstrates that LATS1 plays a key role in maintaining genomic integrity. Mutant LATS1 causes loss of YAP1 oncogene negative regulation and leads to the development of CIN. In addition, Verteporfin has been identified as a targeted cytotoxic agent against LATS1 mutant cells.

Item Type: Dissertation
Supervisor: Régnier-Vigourox, Dr Anne
Date of thesis defense: 3 March 2015
Date Deposited: 01 Jul 2015 09:10
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
610 Medical sciences Medicine
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