University of Dundee

CSC - Mechanisms of chromosome instability in cancer cells

To maintain genetic integrity, human cells must segregate sister chromatids to opposite spindle poles, prior to their cell division. Errors in this process cause cell death and various human diseases, such as cancers and congenital disorders, which are often characterised by chromosome instability and aneuploidy [1]. Evidence suggests that chromosome instability is closely linked to the aetiology of several types of cancers. Moreover, due to chromosome instability, cancer cells rapidly change their phenotypes, which poses major therapeutic challenges.

My group study mechanisms of chromosome segregation in human cells. In particular, by comparing chromosome segregation between normal and cancer cells, we aim to reveal mechanisms of chromosome instability in cancer cells. For example, to ensure correct chromosome segregation in normal cells, duplicated chromosomes must be resolved and subsequently compacted in early mitosis. We have recently developed a novel live-cell imaging assay to study these processes in detail [2]. Once chromosomes are resolved and compacted, chromosomes interact with spindle microtubules. Our recent study has revealed a novel actomyosin-dependent mechanism ensuring efficient and correct interaction between chromosomes and spindle microtubules [3]. Intriguingly the absence of this actomyosin-dependent mechanism is closely correlated with chromosome instability in cancer cells.

In this PhD project, a student will study processes of chromosome resolution and compaction in cancer cells, using the new live-cell assay. Alternatively, he/she will study how the absence of actomyosin-dependent mechanism is causatively linked to chromosome instability in cancer cells. The outcome of this project will provide important information on how chromosome instability occurs in cancers and how chromosome instability can be prevented in cancers. Our project will use advanced methods in cell biology and live-cell microscopy, including super-resolution and light-sheet microscopy. Our project will provide the PhD student with excellent opportunities of training in cancer cell biology and in state-of-the-art microscopy.

References:

1. Funk L.C., Zasadil L.M., and Weaver B.A. Living in CIN: mitotic infidelity and its consequnces for tumor promotion and suppression. Dev Cell 39, 638-52 (2016).

2. Eykelenboom, J.K., Gierlinski, M., Yue, Z., Hegarat, N., Pollard, H., Fukagawa, T., Hochegger, H., & Tanaka, T.U. Live imaging of marked chromosome regions reveals their dynamic resolution and compaction in mitosis. J. Cell Biol. 218, 1531-52 (2019).

3. Booth AJR., Yue, Z, Eykelenboom JK, Luxton GWG, Hochegger H & Tanaka T.U. Contractile actomyosin network on nuclear envelope remants positions chromososomes for mitosis. eLife 8, e46902 (2019).