| dc.description.abstracteng | Chromosome instability (CIN) is a hallmark of human cancer and causes structural (S-CIN) as well as whole (W-CIN) chromosome aberrations. Cancers exhibiting the CIN phenotype are characterized by a large genetic heterogeneity that is associated with an increased adaptability of cancer cells and with a poor patient’s prognosis. In order to improve cancer therapy, it is of particular interest to unravel the mechanisms underlying CIN. Recently, enhanced mitotic microtubule growth rates were identified to contribute to CIN via inducing transient mitotic spindle mis-orientation, thereby triggering an increase in chromosome mis-segregation. Moreover, a pathway containing the microtubule plus-end binding protein EB1, the guanine exchange factor TRIO and its Rho GTPase Rac1, as well as the F-actin regulating Arp2/3 complex was identified to be involved in generation of the spindle orientation defect in cells with increased microtubule plus-end growth rates. However, many links within this pathway were still elusive and their investigation was the main aim of this study.
This study revealed that EB1 and TRIO interact at microtubule plus-ends and that this interaction depends on microtubule dynamics. Moreover, it could be shown that this interaction is required for downstream activation of Rac1 and Arp2/3 in mitotic cells, which in turn results in reorganization of the actin cytoskeleton. Upon hyperactivation of this pathway, such as through increased microtubule plus-end growth rates found in CIN cells, the connectivity and thus density of the actin cortex increases, thereby causing a decreased cortical tension. Since a reduced cortical tension is associated with defects in spindle orientation, this triggers chromosome mis-segregation and thus CIN. Interestingly, an upregulation of TRIO did not only induce whole chromosome instability in an EB1 binding dependent manner via the introduced pathway, but also structural chromosome instability. S-CIN did not only arise through the EB1 binding dependent pathway but also through an EB1 binding independent hitherto unknown pathway. Moreover, TRIO upregulation also resulted in enhanced cell migration in an EB1 binding independent manner. Therefore, these findings do not only give rise to further details and links of a CIN-inducing pathway connecting increased microtubule plus-end growth rates and spindle mis-orientation, but also further confirm and expand the role of TRIO in the development of genetic heterogeneity and metastasis. | de |