Ubiquitin signalling in innate immune responses to pathogens and chronic inflammation in cancer

A key phase of the innate immune system's response to insults (e.g. infection) is to elicit inflammation around the area of the pathogen. Inflammation responses are necessary to allow for the recruitment of immune cells to the region of the body harbouring the pathogen and to stimulate further immune responses that aim to eliminate the pathogen and resolve infection. This process is essential to elicit efficient immune responses and rapidly eliminate invading pathogens and will last between hours and days. In some instances, however, inflammation is not resolved readily and lasts indefinitely becoming itself a cause of disease.

Chronic inflammation can be detrimental to our health on account of the molecules released as part of the immune response also having the capacity to damage our own cells and tissues and also with regards to cancer development. 1 in 6 of all malignancies are thought to be the result of chronic infection, with persistent tumour-promoting inflammation being a Hallmark of Cancer, as laid out by Hanahan and Weinberg. On the other hand, inflammation in the tumour microenvironment can also facilitate anti-tumour immune responses. It is, therefore, key to determine the mechanisms that regulate inflammation in order to be able to supress oncogenic inflammation and hinder tumour growth. A detailed view as to how and when inflammation becomes detrimental may pave the way for novel strategies in cancer therapy.

The aim of this project is, firstly, to determine how non-degradative ubiquitin modifications (small tags added to proteins which may alter their status or elicited functions) facilitate the inflammatory response and are regulated at a mechanistic level. Secondly, this project will aim to determine how these mechanisms are altered in response to a growing tumour compared to primary responses to pathogens.