A large senescent keratinocyte surrounded by smaller transformed cells
Bill Keyes and his team are investigating a process called cellular senescence. This is an irreversible form of cell cycle arrest that prevents the proliferation of damaged cells, thereby acting to prevent cancer. However, this is a complex and organized, dynamic cellular process that also instructs the removal of the damaged cell, and its replacement. Therefore, in certain contexts including embryonic development, regeneration and the protection from cancer, senescence is a beneficial process. However, when not regulated properly, the abnormal accumulation of senescent cells can cause cancer, aging and disease. The Keyes lab uses primary cells, and the mouse and chicken as model systems to investigate the roles and mechanisms of cellular senescence in development, cancer and regeneration.
Cellular senescence is a form of permanent cell cycle arrest that prevents the proliferation of damaged or mutated cells. Initially senescence was discovered when cells reached the end of their replicative lifespan, and more recently have been shown to contribute directly to the aging process. Later, senescence was identified as a potent tumor suppressive mechanism to prevent the continued proliferation of mutated cells. This supports the idea that protection from cancer may contribute to the aging process.
Senescence is a complex and dynamic cellular process, with the cell cycle arrest mediated in part by tumor suppressors such as p53, p21 and p16. In addition, senescent cells remain metabolically active, and secrete a complex mix of factors known as the “senescence-associated secretory phenotype” (SASP), which acts to reinforce the arrest and promote the removal of senescent cells by the immune system. However, additional functions of the SASP including the induction of epithelial-mesenchymal transition (EMT) and proliferation suggested additional more complex roles for the SASP.
Recently, we and others have identified beneficial roles for transient cellular senescence in different contexts. In particular, we identified senescent cells in the developing embryo, in the Apical Ectodermal Ridge (AER) of the limb and in the roof plate of the hindbrain neural tube. Interestingly, these are both major signaling centres that instruct tissue development, plasticity and patterning. In addition, we have also uncovered how transient exposure to the SASP drives cell reprogramming and plasticity, and that this can be beneficial for tissue regeneration. However, when not controlled properly, chronic exposure to the SASP favors cancer stem cell fate and aging.
1) Identification of core mediators of the senescence program
2) To investigate the mechanisms and functions of developmental senescence
3) Identification of the mechanisms by which senescence induces cellular plasticity and regeneration
4) Investigating the contribution of senescence to diseases including cancer and aging
The work from the Keyes lab supports how transient controlled senescence can be beneficial in certain settings such as development and regeneration, and will help to explain how disruption of this cellular program can contribute to aging, cancer and disease.
• 2002: PhD, Dept. Physiology, University of Alberta, Edmonton, Canada. Dr. Esmond Sanders lab.
• 2002-2009: Postdoc, Cold Spring Harbor Laboratory, NY, USA, Dr. Alea Mills lab.
• 2009: Appointed Group Leader at CRG, Barcelona.
• 2016: Appointed Research Director (DR2), INSERM.
• 2016: "Amorçage jeunes équipes" grant from the Foundation for Medical Research (FRM, France)
• 2013: City of Barcelona Prize for Life Sciences
NY Times, Nov 2013
Easy Science Lecture, Contemporary Cultural Centre, Barcelona (CCCB), October 5th, 2011
Oct 2012, Genes Dev.