A Role For Microtubule Dynamics For The Induction Of Chromosomal Instability And Cell Migration And Invasion In Human Cancer Cells

Abstract

Aneuploidy and increased cell migration and invasion are hallmarks of aggressive human cancers. Aneuploidy derives from an increased rate of perpetual chromosome missegregation during mitosis, referred to as chromosomal instability (CIN). CIN contributes to the development of genetic heterogeneity and is thought to support rapid adaptation of cancer cells. Significantly, late tumor stages, which exhibit metastasis, are not only characterized by increased cancer cell migration and invasion, but also by high levels of CIN, both of which correlate with poor patient prognosis. Therefore, I aimed to investigate a potential link between CIN and increased cell migration and invasion in aggressive human cancer cells. In this study, I found that CIN per se is not sufficient to trigger increased cancer cell migration and invasion. However, a hyperactive TRIO-Rac1-Arp2/3 pathway acts as a shared trigger for both, the development of CIN and cancer cell migration and invasion. Hyperactivation of TRIO, Rac1 and the Arp2/3 complex depends on increased microtubule plus-end assembly rates and on the localization of the Rac1-GEF TRIO to microtubule plus-ends via the microtubule end-binding protein EB1. In mitosis, microtubule dependent hyperactivation of the pathway causes spindle positioning defects leading to erroneous microtubule-kinetochore attachments and the generation of lagging chromosomes, which constitute a common cause for chromosome missegregation and CIN. Inhibition of TRIO, Rac1 or the Arp2/3 complex suppressed these phenotypes and prevented the development of aneuploidy in chromosomally instable colon cancer cells. In interphase, the hyperactivity of TRIO, Rac1 and the Arp2/3 complex resulted in highly enhanced cancer cell migration and invasion. Analogous to the situation in mitosis, restoration of proper microtubule dynamics in interphase suppressed the migratory and invasive phenotype in invasive colorectal cancer and melanoma cells. Thus, these results demonstrate a mechanistic link between the regulation of the actin and the microtubule cytoskeleton important for the development of CIN as well as for triggering cancer cell migration and invasion. As one important trigger that can cause increase of microtubule plus-end assembly rates in both, mitosis and in interphase I identified a concomitant loss of the transcription factors p53 and p73. In fact, my studies suggest that p53 and p73 cooperate in maintaining chromosomal stability and suppressing cancer cell migration and invasion.