Control of cell cycle entry in health and disease

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

The Cell Cycle Control team aims to understand how our cells replicate themselves at the right time and in the right place to build our bodies and how dysregulation of these processes leads to cancer. If we understand the control of cell replication in healthy cells and how this control is lost in cancer cells, we can design strategies to specifically prevent cancer cell proliferation, whilst leaving healthy cells unaffected. This strategy would generate kinder cancer treatments by limiting unwanted side-effects and improve outcomes of cancer patients. Understandably, cell replication processes are subject to strict control so that cells are only made when they are needed, for example in an immune response or during wound healing. In the lab, we use healthy cells where we can knockout or add back genes of interest to analyse the effect that gene has on cell replication. To analyse these effects, our team uses high-content microscopes to understand how a cell transitions from a resting (non-replicating) phase to a replicating phase. These microscopes allow us to image 1,000s to 1,000,000s of cells per day such that we can accelerate the investigation of 100s of different genes in cell replication.

Technical Summary

Our group aims to understand how cells control the entry into, and exit from, the cell cycle, in both health and disease. These proliferation-quiescence decisions are poorly understood in mammalian cells, yet getting these decisions right is vital for normal development and tissue homeostasis. Dysregulation of proliferation-quiescence decisions underpins uncontrolled proliferation in tumorigenesis. If we can understand how signalling networks regulating proliferation and quiescence are controlled, then we can design strategies to specifically inhibit cancer cell proliferation or to improve tissue regeneration and improve human health.

We have a number of objectives to achieve our aim. First, we will define the mechanisms that maintain reversibility in quiescence. Second, we will characterise how cell intrinsic and extrinsic factors influence CDK activity in proliferation-quiescence decisions. Finally, we will determine how cancer-specific alterations perturb signalling networks controlling cell cycle entry to drive the continuous proliferation of cells.

To achieve our objectives, we will use our expertise in quantitative, single-cell, time-lapse imaging of human cell lines that we have engineered to express fluorescently-labelled proteins or biosensors. This strategy allows us to simultaneously measure cell cycle entry and the regulatory signalling events in real-time in the same cell. By generating and integrating proteomic and phosphoproteomic datasets with our imaging data, we will work towards a systems-level understanding of proliferation-quiescence decisions in mammalian cells. We will also use our imaging data to parametrise new mathematical models to achieve a mechanistic understanding of the control of proliferation-quiescence decisions. These models will be tested experimentally using genetic (siRNA, CRISPR knockouts, degron tags) and chemical (small molecule inhibitors) perturbations to test the predictive value of our models.

Publications

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