OESOPHAGEAL FATE · Epithelial/Mesenchymal Cross-talk in response to injury and early tumorigenesis; a spatiotemporal perspective
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-06-01 → 2021-05-31
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Epithelial/Mesenchymal Cross-talk in response to injury and early tumorigenesis; a spatiotemporal perspective
Epithelial tissues have evolutionarily adapted to respond to environmental challenges. They must react rapidly to tissue disruption in order to restore the epithelial barrier and ensure survival. Indeed, epithelial stem cells have been shown to present a high degree of fate plasticity in response to tissue perturbation, being this a property by which a cell can take on different and potentially reversible identities. This ability allows a reactivation of their regenerative capacity and ensures rapid restoration of the tissue after damage. However, changes in cell identity require a fine regulation. Unless cell fate dynamics are balanced back to pre-injury levels upon wound healing, inadequate cell activation can lead to epithelial regenerative problems and cancer. Therefore, understanding the molecular pathways governing this finely tuned process will address clinical issues of significant relevance, offering prospects for the development of more adequate targeted therapies. In this project, we aimed to investigate the mechanisms regulating the dynamic changes in the cell fate programme of epithelial cells during tissue regeneration. To this end, we chose the uncomplicated architecture of the mouse oesophagus as an ideal system to investigate the precise mechanisms regulating squamous epithelial plasticity in adults after tissue perturbation. Given the increasing relevance of mesenchymal cells both in tissue maintenance and disease, we paid particular attention to the contribution of the stromal compartment in the regulation of epithelial fate changes. On completion of this action, our work has identified distinct changes in epithelial cell behaviour in a model of oesophageal tissue injury, unveiled relevant regulatory mechanisms underlying epithelial cell fate transitions, and described the contribution of the niche in defining epithelial cell plasticity and fate identity.
Data: CORDIS, © European Union
Project objective
Epithelial tissues have evolutionarily adapted to rapidly react to tissue disruption in order to restore the epithelial barrier and ensure survival. The dynamic behaviour of epithelial cells in response to injury represents a decisive mechanism to recover tissue integrity. Following injury, not only cycling but also differentiating epithelial cells are able to revert back, reacquiring stem cell-like behaviour and contributing to tissue regeneration. Although this cellular plasticity is normally a strictly controlled and limited process, if inadequately activated in cells with pre-existing tumour-initiating mutations it will have implications for cancer development.In this proposal, I will investigate the little-known mechanisms governing the dynamic changes in epithelial cell behaviour in the events after tissue injury using the uncomplicated architecture of the oesophagus as a model. The aim is to identify molecular regulators governing cell fate switching following the early wound response, and ultimately, reveal their potential relevance for early epithelial tumour formation. Given the increasing relevance of the mesenchymal compartment both in tissue maintenance and disease, I will particularly focus on the contribution of epithelial-mesenchymal cross-talk in the regulation of epithelial fate changes. To this end, I present an innovative approach that combines precise lineage tracing cell fate data with spatiotemporal single-cell whole transcriptomics. This approach relies on cutting-edge techniques and transgenic animal models widely established in the host laboratory that, when combined, will enable the identification of rules regulating behaviour of epithelial cells with temporal and spatial resolution.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union