Regulation Of Spindle Orientation By A Mitotic Actin Pathway In Chromosomally Unstable Cancer Cells

by Nadine Schermuly
Doctoral thesis
Date of Examination:2020-01-07
Date of issue:2020-11-18
Advisor:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Jörg Großhans
Persistent Address: http://dx.doi.org/10.53846/goediss-8319

 

 

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Abstract

English

Aneuploidy is a hallmark of human cancer and is observed in 90 % of solid tumors. The perpetual gain or loss of whole chromosomes, defined as chromosomal instability (CIN), represent one mechanism causing aneuploidy. CIN cells are characterized by genetic heterogeneity, which allows the development of therapy resistance and promotes tumorigenesis. Thus, poor prognosis and patient’s outcome is associated with CIN. Recently, it was revealed that CIN cells exhibit increased microtubule plus-end assembly rates during mitosis, which lead to spindle geometry defects, thereby facilitating the generation of lagging chromosomes and finally causing CIN. Moreover, first results revealed a role of a hyperactive TRIO-Rac1-Arp2/3 pathway mediated by increased microtubule dynamics during mitosis, which promotes spindle misorientation. Thus, the purpose of this study was to further analyze the role of a TRIO-Rac1-Arp2/3 pathway and how it causes spindle misorientation in CIN cells. The present study revealed that CIN cells are characterized by a transient spindle axis misalignment during prometaphase, caused by enhanced microtubule plus-end assembly rates in mitosis, which finally leads to chromosome mis-segregation and CIN. The pathway causing spindle axis misalignment and chromosome mis-segregation in CIN cells was already identified previously (Berger, 2016). However, this work revealed that a mitotic EB1 dependent TRIO-Rac1- Arp2/3 pathway in response to enhanced microtubule plus end assembly rates leads to increased actin polymerization, which reduces cortical tension in mitotic CIN cells. Moreover, the present study indicates that a RhoA-formin pathway leading to unbranched actin polymerization ensures proper cortical tension, and thus accurate spindle axis alignment in prometaphase. This pathway is active in both, chromosomally stable and unstable cells whereby in CIN cells, due to enhanced microtubule plus-end assembly rates, a TRIO-Rac1-Arp2/3 pathway deregulates mitotic actin cortex structures, which impairs the generation of cortex tension required for proper spindle axis alignment in prometaphase. Thus, these results demonstrate that a microtubule triggered actin pathway during mitosis causes spindle axis misalignment and chromosome mis-segregation in CIN cells.
Keywords: Cancer; Chromosomal Instability; Spindle Orientation; Microtubule; Actin; Rac1; Arp2/3; TRIO; Cortex Tension; Cortex Architecture; Spindle Axis Misalignment
 
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