Investigating the role and molecular mechanisms of two distinct cell death modalities in cutaneous regenerative and neoplastic inflammation

Acute and chronic wounds predispose tissues to tumour formation, but the association between
reparative and neoplastic immune responses is poorly understood. In this project, we aim to
understand the role of two immune mediators, namely HMGB1 (High Mobility Group Box-1) and
ATG (autophagy-related gene) 16L1, in the initiation and progression of non-melanoma skin
tumours.
My preliminary data show that NETosis, a type of cell death that uniquely occurs in neutrophils - the
first immune cells that are recruited into wounds- is regulated by the danger-associated molecule
HMGB1. Here, we aim to block NETosis and its upstream regulators in order to facilitate wound
healing while blocking tumour formation in the skin and to gain insight into the signalling pathways
controlling NETosis.
In a second aim I will focus on the role of autophagy, another cell death-associated process, in
mediating skin inflammation and tumour formation. Our preliminary data show that skin tumours
develop faster when ATG16L1, a protein that is crucial for the execution of autophagy, is lacking
from the epithelial cells of the skin. We aim to shed light on the molecular mechanisms that drive
tumour formation in the absence of autophagy and investigate the effect of autophagy on epithelial
stem cell activation. This research will give insight into the molecular crosstalk that mediates the
early events leading to tumour formation, at a stage where it might still be possible to keep the
disease at bay.