The role of Wnt signalling in the microtubule-mediated maintenance of chromosomal stability

by Alexander Haas
Doctoral thesis
Date of Examination:2024-05-06
Date of issue:2024-07-05
Advisor:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Heidi Hahn
Persistent Address: http://dx.doi.org/10.53846/goediss-10554

 

 

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Abstract

English

Chromosomal instability (CIN) is a major hallmark of cancer and represents a driving force for tumourigenesis, tumour progression, and the development of therapy resistance. CIN can be subdivided into structural CIN (S-CIN) and whole chromosomal CIN (W-CIN), which lead to structural and numerical chromosomal aberrations, respectively. While S-CIN is caused by DNA replication stress and DNA repair defects, W-CIN is triggered by mitotic errors. Previously our group showed that abnormally increased mitotic microtubule growth rates are responsible for perpetual chromosome missegregation, thereby causing aneuploid karyotypes in human cancer cells. Furthermore, these increases in microtubule polymerisa tion are triggered by replication stress that is detected in chromosomally unstable human cancer cells, which might explain the concomitant occurrence of S- and W-CIN. Interest ingly, the search for players in microtubule-regulated W-CIN has yielded basal Wnt10b/LRP signalling as a key suppressor of abnormally increased microtubule growth rates and the subsequent evolvement of aneuploidy. However, the mechanism by which Wnt signalling influences mitotic chromosome segregation is still unknown. This study shows that Wnt10b is the main Wnt ligand required for maintaining microtu bule-mediated chromosomal stability. Wnt10b acts specifically during early S phase, where loss of Wnt10bsignalling causes immediate increases in microtubule polymerisation without affecting replication dynamics per se. Also, activation of Wnt10b signalling rescues abnor mal microtubule polymerisation rates and chromosome missegregation upon replication stress after its experimental induction or in chromosomally unstable cancer cells that suffer from endogenous replication stress. Interestingly, this study showed that increased micro tubule assembly rates are triggered during early S phase and remain elevated until mitosis, where they promote chromosome missegregation and aneuploidy. Importantly, increased microtubule polymerisation rates regulated by Wnt10b signalling during early S phase cause replication stress-associated chromosomal breaks and gaps thereby contributing to S-CIN. Thus, this study uncovered a novel early S phase-specific link between Wnt10b signalling and replication stress in regulating the microtubule cytoskeleton, which in turn regulates the occurrence of S- and W-CIN.
Keywords: Wnt10b; Wnt signalling; chromosomal instability; colorectal cancer; microtubule polymerisation rate