Senescence research group

OUR SCIENCE: THE BASICS
OUR SCIENCE: THE DETAIL

OUR SCIENCE: THE BASICS

“How does cellular senescence influence cancer and ageing?”

Senescence is a cellular response activated by different stresses such as replicative exhaustion, damage to their DNA, oncogenic activation or inflammation. As part of the senescence programme, cells exit the cell cycle. This stops old, damaged or cancerous cells from replicating incorrectly. Cells undergoing senescence also change their morphology, undergo a significant reorganization of their DNA, rewire their metabolic processes and secretes specific proteins (what is called the Senescence-Associated Secretory Programme, SASP). The SASP allows senescent cells to communicate with their neighbours but also can disrupt tissue homeostasis and contribute to cancer and ageing

Our research is looking to better understand how cells control senescence, and what is the role of senescence in cancer and ageing. We combine high-throughput functional screens (where we can test thousands of interventions) with mechanistic analyses to understand how senescence is regulated and how we can manipulate senescent cells. We use cultured cells and also study how our discoveries apply to models of cancer and ageing.

Eventually, we analyse clinical samples to understand the connection between our observations and the development of age-related human diseases. By better understanding how senescence is initiated and regulated, we can hopefully help improve therapies to treat cancer, many age-related diseases (such as pulmonary fibrosis and metabolic diseases) and aging.

OUR SCIENCE: THE DETAIL

“Senescence influences multiple biological processes including ageing and cancer.”

Cellular senescence is a stress response induced by oncogene activation, chronic inflammation, telomere erosion or DNA damage. Senescent cells activate a dynamic transcriptional programme leading to stable cell cycle exit, chromatin reorganization, metabolic reprogramming and the establishment of a senescence-associated secretory programme (SASP). Acute induction of senescence is a physiological response that limits fibrosis and acts as a potent tumour suppressor mechanism. However, the abnormal accumulation of senescent cells contributes to ageing and many diseases, including cancer. Recently, strategies aimed to selectively eliminate senescent cells (senolytic therapies) have been shown great promise for the treatment of a wide-range of diseases.

The goal of my research program is to elucidate the molecular mechanisms that implement and regulate senescence. We intend to exploit this knowledge to devise novel strategies that target senescence in age-related pathologies, especially cancer. To investigate senescence, we combine high-throughput screens and mechanistic analyses in cell culture, with in vivo analyses in mouse models. We then analyse clinical samples to uncover the relevance of our observations for human disease.

My research programme has two overarching aims: (1) Uncover novel (epi)genetic mechanisms controlling senescence. We will use functional (CRISPR, RNAi and drug) screens, proteomic and genomics to identify trans factors and cis elements that control senescence and elucidate how they function. (2) Investigate how the SASP mediates the effects of senescence. We will perform screens to discover regulators and functions of different subsets of the SASP (e.g. pro- inflammatory or fibrotic) and use novel mouse models to uncover the roles of the SASP in ageing and disease. Connecting both aims, we will search for vulnerabilities of senescence. We are actively collaborating with several companies to pursue novel ways to target senescence cells as a direct result of our research. By better understanding how senescence is regulated and implemented, we expect that our research will inform therapies that harness senescence in cancer and ageing.