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Cell News 2/2015
PRIZE WINNERS
BINDER INNOVATION PRIZE 2015
Altered microtubule dynamics triggers
chromosomal instability and aneuploidy in
human cancer cells
Holger Bastians
Georg-August University Göttingen, Göttingen Center for Molecular Biosciences (GZMB) and Univer-
sity Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Grisebachstraße 8,
D-37077 Göttingen, Germany, Email:
Phone: ++49-551-3933823
Summary
Chromosomal instability (CIN) is defined as the perpertual gain
or loss of whole chromosomes during mitotic cell division and
represents a major hallmark of human cancer. This defect, which
leads to evolving aneuploidy, is tightly associated with the ma-
lignancy and aggressiveness of tumors. It is thought that CIN
provides a high adaptation potential to cancer cells, which is
crucial for tumorigenesis, tumor progression and for the deve-
lopment of therapy resistance. Therefore, it is of utmost impor-
tance to understand in detail why and how cancer cells gain
or loose whole chromosomes during mitosis to allow the deve-
lopment of therapeutic strategies targeting the mechanisms of
chromosome missegregation in cancer cells. Most recently, we
identified a key mechanism that causes perpetual chromosome
missegregation in cancer cells. We found that mitotic spindles
in cancer cells exhibiting CIN are characterized by an increa-
se in microtubule plus end dynamics. In particular, abnormally
elevated microtubule assembly rates represent a key trigger for
chromosome missegregation by inducing transient geometry
and positioning defects of the mitotic spindle. This, in turn, faci-
litates the formation of erroneous microtubule-kinetochore in-
teractions during mitosis leading to the generation of so-called
lagging chromosomes during anaphase and subsequent chro-
mosome missegregation. Importantly, restoring normal micro-
tubule plus end assembly rates is sufficient to suppress spindle
defects, kinetochore mal-attachments, chromosome missegre-
gation and thus, the CIN phenotype in otherwise chromosomally
instable cancer cells. Hence, our results identified a key trigger
for CIN in cancer cells and open up new opportunities for thera-
peutic options that are based on CIN suppression.
Introduction
The overwhelming majority of human cancer cells is characte-
rized by the presence of various forms of genetic instability, which
include increased rates of gene mutations as well as structural
and numerical chromosome aberrations (Lengauer
et al.
, 1998).
In particular, numerical chromosome aberrations, i.e. whole chro-
mosome aneuploidies, are highly abundant and can affect up to
25% of the entire cancer cell genome (Beroukhim
et al.
, 2010).
Interestingly, the presence of aneuploidies in cancer cells is not
a new observation, but was already recognized by David Paul von
Hansemann and Theodor Boveri at the end of the 19th centu-
ry (Hansemann, 1890; Boveri, 1914). Morever, it was Boveri, who
postulated in 1914 that a scrambled composition of chromoso-
mes is crucial for cancer development (Boveri, 1914). Today, it is
well established that aneuploidy in cancer cells is the result of
perpetual gains or losses of whole chromosomes during mitosis.
In fact, cancer cells show an increased rate of ongoing chromo-
some missegregation and this process is referred to as chromoso-
mal instability (CIN). Importantly, the experimental induction of
aneuploidy in various mouse models, in which, for instance, the
mitotic spindle checkpoint is weakened, have supported Boveri´s
hypothesis and demonstrated that aneuploidy can indeed contri-
bute to tumorigenesis and tumor progression (Schvartzman
et al.
,
2010). In addition, analyses of large numbers of human tumors
showed that aneuploidy is tightly associated with malignancy and
aggressiveness of tumors and with the development of therapy re-
sistance in patients (McGranahan
et al.
, 2012). Thus, CIN and an-
euploidy represent hallmark phenotypes of human cancer, which
can contribute to tumorigenesis and tumor progression. However,
although a long-standing question, the molecular mechanisms
causing CIN are still not well understood.
