Mammalian cells contain a skeleton named cytoskeleton that is responsible for shaping them and giving them mechanical resistance. The cytoskeleton is formed by a network of different proteins, actin being one of them. The actin cytoskeleton is organized by actin filaments which can grow (polymerize) and shorten (depolymerize) by adding or removing molecules of actin. Hence, the actin cytoskeleton is highly dynamic and allowing cell shape changes to adapt to its environment, gives continuous structural support and is involved in many essential cellular processes such as migration and contraction. These processes need the controlled interplay of different proteins with actin. Regulation of actin dynamics can happen at different levels, from actin gene expression to actin polymerization or degradation. We have found that one of the pathways controlling actin dynamics is also involved in preventing cells from replication, causing what is known as cellular senescence.
Cells self-replicate to generate an increased number of cells. To do so they undergo a process known as the cell cycle which involves the duplication of all cell components, followed by the physical separation of the original cell into two identical daughter cells. The cell cycle is a tightly regulated multistep process which has distinct checkpoints to ensure no errors are inherited to the daughter cells. If one of these checkpoints is not passed, cells will arrest their proliferation and no-longer self-replicate. As a consequence, cells will die (apoptosis) or enter a permanent state of cell cycle arrest named cell senescence. Cell senescence was first observed in laboratory cells which could not continuously replicate and have stopped further division. Later it has been shown that damaged cells can also enter cell cycle arrest or senescence. Therefore, cell senescence can actually be beneficial during tissue remodelling, cancer, fibrosis or aging to prevent proliferation of damaged cells. There are also physiological senescence states, such as experienced by melanocytes when forming nevi. Melanocytes are pigmented cells in the skin that, when certain genetic alterations or mutations are present, can first proliferate and then enter senescence. Accumulation of senescent melanocytes in the skin is observed as nevus. These senescent melanocytes can subsequently reactivate proliferation and generate tumours, known as melanomas.
In this project we aim to unravel how decrease dysregulation of the actin machinery and dynamics causes cells to senesce, and how this could influence melanoma development and progression. Cell senescence is important in certain diseases such as fibrosis or cancer. Therefore, the study of this process is of clinical interest. This proposal wants to study a new mechanism for cell senescence and the results of this project are potentially interesting to investigate new drugs or therapies to modulate the senescence process in these diseases.
The overall objectives of this project have been:
To find the mediators and components involved in cell senescence when actin machinery is not dysfunctional.
To study whether this form of senescence affects different cell types equally
To investigate how this new senescence mechanism affects melanoma progression
