The role of the AURORA-A oncogene in tumorigenesis and in the therapy response in colorectal and rectal cancer
Zusammenfassung der Projektergebnisse
AURORA-A encodes for a kinase that localizes specifically to mitotic centrosomes and to the mitotic spindle and fulfills various functions for the entry and during progression of mitosis. Importantly, the AURORA-A gene is frequently overexpressed in colorectal cancer, which is due to a gain of chromosome 20q where the AURORA-A locus is located indicating that AURORA-A represents a putative oncogene. However, the molecular consequences of AURORA-A overexpression in cancer are little understood. In our project we investigated the role of AURORA-A overexpression in colorectal cancer cells. We discovered that elevated levels of Aurora-A cause perpetual mis-segregation of whole chromosomes, a phenotype referred to as chromosomal instability (CIN). CIN is a major hallmark of CRC and of many other cancers, leading to the generation of aneuploidy, which evolves further over time. The ongoing gain or loss of whole chromosomes results in a high genetic heterogeneity in tumors and thus, contributes to tumor evolution. Our discovery showed that overexpression of AURORA-A causes CIN in CRC and might thereby contribute to tumor progression and also to the development of therapy resistance. Furthermore, we investigated the molecular mechanisms leading to the induction of CIN upon AURORA-A overexpression in CRC cells. By analyzing mitotic progression, mitotic spindle assembly and microtubule dynamics in live cell microscopy experiments we found that overexpression of AURORA-A results in increased microtubule plus end assembly rates within mitotic spindles. Moreover, this defect causes transient spindle orientation defects that facilitate the generation of hyper-stable erroneous microtubule-kinetochore attachments, which subsequently results in chromosome mis-segregation and CIN. Intriguingly, we found that the phenotype of increased microtubule assembly rates was generally detectable in CRC cell lines exhibiting CIN whereas CRC cells with MIN/MSI showed normal microtubule growth rates in mitosis. This indicates a general role of abnormal microtubule dynamics for the generation of CIN. However, increased microtubule assembly rates were also detected in CRC cells without AURORA-A overexpression, but in these cases the defect leading to CIN was strictly dependent on Aurora-A activity. This suggested that Aurora-A is hyper-active in CRC cells also in the absence of its overexpression. In fact, we found that loss of the Chk2-BRCA1 tumor suppressor pathway can cause hyper-activity of Aurora-A localized to mitotic centrosomes. Consequently, loss of CHK2 or loss of the Chk2-mediated phosphorylation of BRCA1 results in increased microtubule plus end assembly rates, very similar to the situation seen upon overexpression of AURORA-A. Hence, in addition to its overexpression, additional genetic aberrations in CRC can cause increased Aurora-A activity, which triggers abnormal microtubule dynamics and CIN.
Projektbezogene Publikationen (Auswahl)
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Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nature Cell Biology. 2014;16: 779 – 91
Ertych N, Stolz A, Stenzinger A, Weichert W, Kaulfuß S, Burfeind P, Aigner A, Wordeman L, Bastians H
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A phenotypic screen identifies microtubule plus end assembly regulators that can function in mitotic spindle orientation. Cell Cycle. 2015;14: 827-37
Stolz A, Ertych N, Bastians H
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The CHK2-BRCA1 tumor suppressor axis restrains oncogenic AURORA-A to ensure proper mitotic microtubule assembly. Proc Natl Acad Sci USA. 2016 Feb 16;113(7):1817-22
Ertych N, Stolz A, Valerius O, Braus GH, Bastians H
