Proteotoxic stress, p53 and cell competition: mechanisms and impact on tissue colonisation

Speaker Professor Eugenia Piddini, Wellcome Trust Senior Research Fellow, School of Cellular and Molecular Medicine, University of Bristol

Title Proteotoxic stress, p53 and cell competition: mechanisms and impact on tissue colonisation

Host Jody Rosenblatt

 

Abstract 

My group’s main research interest is to understand how cell competition shapes tissues colonization in cellular communities. We and others have shown that cell competition plays a major role in determining the cellular composition of adult tissues in health and disease. By eliminating slow-growing and mis-specified cells, it likely contributes to tissue fitness and perhaps delays the onset of ageing and disease.

However, it is also exploited by tumor cells to kill their neighbours and promote their own expansion. By unveiling the mechanisms of action of cell competition and its impact on adult tissue colonization we aim to power the use of this biological process for therapeutic purposes. Towards that general aim, my group has taken two complementary approaches: one that builds on our strengths in Drosophila genetics to identify pathways directly relevant in vivo, and another that exploits live imaging and the ease of mammalian cell manipulation in vitro to study the dynamics of this process and provide a platform to test mammalian relevance. Our work has demonstrated that cell competition plays a role in adult tissue homeostasis, in cancer growth and in epithelial repair.

We also discovered several new mechanisms and molecular mediators of cell competition: we identified a new role for the JAK/STAT pathway in cell competition and implicated JNK signalling and the Hippo pathway in tumor/host cell competition; we discovered mechanical cell competition and identified p53 as a key modulator of this type of cell competition; we also discovered that the oxidative stress response and proteotoxic stress are leading causes of cell competition. In addition to shedding light on the fundamental mechanisms that cells use to compete, these discoveries provide a molecular swiss army knife of possible interventions to control and modify tissue colonization outcomes for therapeutic applications, in cancer and in regenerative medicine.