The shape of cells to come

Cell division is often framed in terms of DNA replication, but in reality multiple components of a cell must be duplicated and carefully segregated to daughter cells each time it divides. And while textbook diagrams provide a two-dimensional view of chromosomal segregation, cells exist in three dimensions - and the three-dimensional shape of cells is turning out to be a critical factor in control of cell division.

Although cells come in all shapes and sizes, when they begin to divide, they typically round up and shed many of their attachments to their underlying substrate. These shape changes are driven by remodelling of the actin cytoskeleton, a process initiated by the master controllers that regulate entry into mitosis, the Cdk1/cyclinB complex - ensuring that rounding is coordinated with other key aspects of cell division [1]. The cytoskeletal remodelling generates a rigid protective shell that enables the mitotic spindle to assemble and guides spindle orientation [2].

In addition, Professor Baum and colleagues have recently shown that, although most substrate contacts are remodelled to allow rounding to occur, cells use integrins to maintain contact with their substrate throughout mitosis. Indeed, mitosis is disrupted if these integrin contacts are lost [3].

As the details of normal cell division are being elucidated, it is becoming clear that cancer cells do not follow the rules. Cell division is normally tightly controlled and, in organised tissues, cells are highly sensitive to signals from cells that surround them. In cancer, cells typically ignore these signals, showing a tendency to round up and divide autonomously, and acquire the capacity to divide even when not in contact with a substrate.

Furthermore, in their natural settings, cancer cells are typically embedded in tissues - particularly epithelial tissue - and have to overcome the physical constraints imposed by this higher-order organisation. Professor Baum's group has examined how the physical forces imposed by tissue organisation affect cell division [4]. Now, in collaboration with engineers and colleagues in the UCL Institute for the Physics of Living Systems, his group has developed experimental tools to finely control the forces applied to cells, to determine precisely how cell division is affected by compression, stretch and other physical forces.

Although cancer cells are clearly using the same machinery of cell division, they are using it in a different way. Professor Baum's group has also begun to explore how oncogenic mutations affect the intracellular mechanics of mitosis, which intracellular signalling pathways are mediating these effects, and how they respond to the kinds of physical forces they are likely to be exposed to in body tissues.

The work is a reminder that cancer cells do not exist in isolation, and that tumours are complex three-dimensional structures. One sobering realisation is that the physical form of tumours can be highly variable - something that oncologists and surgeons are well aware but can be overlooked in the drive to understand dysregulated biochemical pathways in the cell. Ultimately, a deeper understanding of the factors controlling normal cell shape will reveal the constraints that cancer cells must overcome in order to divide so promiscuously - insight that could point the way to new therapeutic interventions.

1. Matthews HK et al. Changes in Ect2 localization couple actomyosin-dependent cell shape changes to mitotic progression. Dev Cell. 2012;23(2):371-83.
2. Lancaster OM et al. Mitotic rounding alters cell geometry to ensure efficient bipolar spindle formation. Dev Cell. 2013;25(3):270-83.
3. Dix CL et al. The role of mitotic cell-substrate adhesion re-modeling in animal cell division. Dev Cell. 2018;45(1):132-145.e3.
4. Wyatt TP et al. Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc Natl Acad Sci USA. 2015;112(18):5726-31