Human Cell Division in normal and cancer cells
Our group investigates the fundamental mechanisms of cell division, and the deregulation of these processes in cancerous cells. 85% of solid human cancer tissues have an imbalanced number of chromosomes (aneuploidy) and have an elevated tendency to loose or gain chromosomes. Chromosomal instability and aneuploidy are not only symptoms of cancer cells, they can directly cause or enhance cancer formation, by creating dosage imbalances between oncogenes and tumor suppressors, and contributing to the development of cancer drug resistances.
In our fundamental work we study the assembly and the function of the mitotic spindle. The mitotic spindle is a microtubule-based structure that segregates sister chromatids during cell division. Microtubules are bound with their minus-ends to the spindle poles, which are each associated to a centrosome. At the dynamic plus-ends these microtubules can be free (astral microtubules), they can contact the cell cortex, they can form anti-parallel arrays with microtubules emanating from the other spindle pole (inter-polar microtubules), or they can bind to chromosomes via kinetochores (kinetochore-microtubules). These microtubule-binding platforms move chromosome and block mitotic progression in case of erroneous kinetochore-microtubule attachments via the spindle assembly checkpoint.
Our aim is to understand how the different components of the mitotic spindle coordinate their function to establish a proper bipolar spindle and achieve a faithful segregation of sister chromatids. Our research has focused on the regulation and organization of kinetochore-microtubules (Amaro et al., 2010; Vladimirou et al., 2013; Dudka et al., 2018), the establishment and orientation of the mitotic spindle (Toso et al. 2009; Mchedlishvili et al., 2012; Lee et al., 2018); and the role of the centrosome within the spindle (Tan et al. 2015; Gasic et al. 2015; Meraldi 2016). Moreover our aim is to understand how these processes are affected in a cancer cell setting (Thoma et al., 2009, Gulluni et al., 2017).
Our studies rely on high-resolution quantitative fluoresence microscopy, extensive image analysis combined with chemical and genetic perturbations, cell biology, and biochemistry. Many of our studies are carried out in national and international collaborations.
Amaro AC, Samora CP, Holtackers R, Wang E, Kingston IJ, Alonso MC, Lampson MA, McAinsh AD, and Meraldi P (2010). Molecular control of kinetochore-microtubule dynamics and chromosome oscillations. Nat Cell Biol 12, 319–329.
Dudka D, Noatynska A, Smith CA, Liaudet N, McAinsh AD and Meraldi P (2018) Complete microtubule-kinetochore occupancy favours the segregation of merotelic attachments Nat Commun. 9:2042. doi: 10.1038/s41467-018-04427-x
Gasic I, Nerurkar P and Meraldi P (2015) Centrosome age regulates kinetochore microtubule stability and biases chromosome mis-segregation, Elife, doi: 10.7554/eLife.07909
Gulluni F et al (2017). Mitotic spindle assembly and genomic stability in breast cancer require PIK3-C2scaffolding function Cancer Cell, 2017, 32, 444-459
Lee BY, Schwager F, Meraldi P and Gotta M. (2018) p37/UBXN2B regulates spindle orientation by limiting cortical recruitment via PP1/Repo-Man J. Cell Biol., 217, 483-493
Mchedlishvili N, Wieser S, Holtackers R, Mouysset J, Belwal M, Amaro AC and Meraldi, P (2012). Kinetochores accelerate centrosome separation to ensure faithful chromosome segregation. J Cell Sci 125, 906–918.
Meraldi P (2016) Centrosomes in spindle organization and chromosome segregation: a mechanistic view, Chromosome Res, 24, 19-34
Tan CH, Gasic I, Huber-Reggi SP, Dudka D, Barisic M, Maiato H and Meraldi P (2015) The equatorial position of the metaphase plate ensures symmetric cell divisions, Elife, doi: 10.7554/eLife.05124
Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, Hergovich A, Moch H, Meraldi P, and Krek W (2009). VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11, 994–1001.
Toso A, Winter JR, Garrod AJ, Amaro AC, Meraldi P and McAinsh AD (2009). Kinetochore-generated pushing forces separate centrosomes during bipolar spindle assembly. J Cell Biol 184, 365–372.
Vladimirou E, Mchedlishvili N, Gasic I, Armond JW, Samora, CP, Meraldi P and McAinsh AD (2013). Nonautonomous movement of chromosomes in mitosis. Dev Cell 27, 60–71.