About Our Lab:
Cancer is a disease of excessive cell division, with cancer cells proliferating uncontrollably, leading to the disruption of normal tissue function and ultimately death. Our lab uses a combination of cutting edge quantitative live and fixed microscopy using novel fluorescent biosensors, phosphoproteomics and flow cytometry to analyse the mechanisms controlling how cells proliferate and how these are disrupted in cancer to drive cancer progression, chromosome instability, drug resistance and metastasis.
The Cell Cycle
The cell cycle consists of five parts, two ‘active’ phases (S and M), two gap phases (G1 and G2), and a quiescent state (G0). G1 phase involves the synthesis of proteins required for DNA replication and increasing the cell size. This is followed by S phase where the cell makes a complete and identical copy of its genomic DNA. Once replication of the DNA is complete the second gap phase (G2) ensues and the cell prepares itself for mitosis (M), where the DNA condenses to form chromosomes, which are then separated into two identical daughter cells.
What is so Important about the Cell Cycle ?
De-regulation of the cell cycle is a common event in a wide variety of human diseases, such as arthritis, neurodegenerative, cardiovascular disease and of course cancer, which is often described as a “disease of the cell cycle”.
Many of the genes that are commonly deregulated in cancer are critical regulators of the cell cycle (e.g. Rb, p53, ATM, Cdk’s, p16).
What is Mitosis ?
Mitosis is the most active and arguable the most visually exciting phase of the cell cycle.
There are 5 main stages of Mitosis;
1) Prophase, 2) Pro-Metaphase, 3) Metaphse, 4) Anaphase, and 5) Teleophase.
Upon the completion of Mitosis cytokinesis occurs.
Why Study Mitosis ?
Just like the other phases of the cell cycle, many of the genes involved in regulating this critical phase are deregulated in human diseases, especially cancer. Mitosis is an incredibly rapid and complicated orchestra of events that requires absolute precision. Defects during mitosis tightly correlate with chromosomal/genomic instability, a hallmark of cancer, especially the more aggressive and metastatic forms. Normal cells have ‘checkpoints’ that prevent mitotic errors from being passed on by delaying division to allow time to either repair the damage or sacrifice themselves (via apoptosis). In contrast, cancer cells often have defective checkpoints and thus fail to delay. This provides cancer cells with a growth advantage, but it is also a weakness as they are no longer able to respond correctly to particular cellular insults. Thus identifying these defects and targeting them should provide a way to selectively kill cancer cells. In fact, a number of classical chemotherapeutic drugs (e.g. Taxol) work this method to selectively kill cancer cells.
While our knowledge of mitosis has and continues to increase dramatically, it is still incomplete. Furthermore, we still have a long way to go in translating this knowledge into improved therapies.
1) Targeting MASTL kinase, a novel breast cancer oncogene.
A primary driving force behind the initiation and ongoing development of breast cancer is the activation of oncogenes. Oncogenes act like a car accelerator, driving excessive growth and spreading of the cancer cells throughout the body. Consequently, identifying new oncogenes and determining their functions is essential for understanding how breast cancers grow and spread. We recently identified a novel oncogene called MASTL that is amplified and over-expressing up to 45% triple-negative breast cancers (TNBC). This project aims to better understand the mechanisms by which MASTL drives breast cancer and to establish the tools necessary to develop specific inhibitors of MASTL that could be used to treat breast and other cancers.
2) Understanding Platinum Resistance in Cancer.
We have recently identified several novel signalling pathways involved in regulating platinum resistance in Lung Cancer (Marini et al. Sci Trans Med, 2018). To better understand these innate resistance mechanisms, we have generated several novel fluorescent biosensor cell lines to provide real-time readouts of cell cycle status, mitotic fidelity and DNA damage and repair kinetics in single cells, which will be combined with detailed phosphoproteomic analysis of the cellular responses to platinum. The goal of this project is to determine the exact mechanism by which individual cells escape platinum mediated cell death, and to identify novel, rational sensitisation pathways to exploit and improve platinum based chemotherapy.