Chromosome segregation errors: a double-edged sword - TI Pharma

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Thesis summary
Unequal separation of the mother cells’ DNA over its two daughter cells upon cell division is
a prevalent phenotype found in cancer cells. This imbalanced nuclear division manifests itself
as chromosome segregation errors in anaphase and telophase, the final phases of Mitosis.
Chromosome unstable (CIN) cancer cells continuously display chromosome segregation errors,
which leads to an abnormal chromosome number, termed aneuploidy, in the cancer cells’ progeny.
Research described in this thesis suggests that CIN is a ‘double edged sword’. Although single gains
and losses of certain chromosomes could lead to tumor growth promoting effects, severely enhanced
levels of CIN unequivocally kills all cells. It is generally hypothesized that single chromosome
missegregations can induce gain of certain oncogenes or loss of tumor suppressor genes and
thereby stimulate tumorigenesis. Chapter 2 of this thesis describes another mechanism by which
chromosome segregation errors could enhance tumorigenesis. Cleavage furrow ingression in the
presence of a single chromosome missegregation event, can lead to double strand breaks when the
chromosomes is lagging behind in telophase. These double strand breaks were found to result in
structural chromosomal changes in the progeny of the missegregating cells, suggesting that CIN not
only enhances tumorigenesis by inducing aneuploidy, but also by introducing breaks in the chromatin.
To determine the effects of CIN in vivo we developed two mouse models (Chapter 3), which each
conditionally express a mutant form of the mitotic checkpoint kinase Mps1. Mps1 is essential for the
fidelity of cell division and inhibition of its function results in chromosome segregation errors. With
the use of these two mouse models, we will be able to to test the influence of various levels of CIN on
tumor initiation, progression and, upon induction of severe CIN, also tumor growth inhibition.
The second part of this thesis describes the possibilities of exploiting CIN in anti-cancer strategies
(reviewed in Chapter 4). Although severe levels of CIN eventually leads to cell death in any
cell type, data in Chapter 5 and 6 demonstrate that partial depletion or inhibition of Mps1
kinase activity could be tumor cell selective. In addition, we show in Chapter 5 that partial
Mps1 depletion synergizes with the clinically used chemotherapeutic Paclitaxel (Taxol) in killing
tumor cells. By employing the mouse models described in Chapter 3 and the Mps1 inhibitor
described in Chapter 6, we wish to address the question whether Mps1 inhibition in vivo also
results in tumor cell specific cell death and could therefore, in the future, be used in the clinic.
The final experimental chapter, Chapter 7, demonstrates the use of intravital imaging as a tool to
determine in vivo responses to chemotherapeutics. We developed a system to simultaneously image
mitotic progression and apoptotic responses in the same cells in vivo. Using this system we find, in
contrast to the generally accepted idea of Taxane’s mode of action, that systemic Docetaxel (a semisynthetic
Taxane) treatment kills tumor cells in vivo independently of defects in mitotic progression.
These data question the usefulness of anti-mitotic drugs in anti-cancer treatment and are being
discussed in light of the recent literature in Chapter 8 of this thesis, in addition to CIN’s ‘double edged
sword’.
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