Lay Abstract
The matrisome is the “glue” that exists between our cells, which provides supportive scaffolding and defines the structure of tissues. It has been shown that components of the matrisome provide signals to guide the behaviour of nearby cells. A number of studies indicate that these signals can also determine whether tumour cells become aggressive or respond to 3 anti-cancer drugs, and thus variations in the makeup of the matrisome surrounding tumours may explain why some patients have progressive disease or fail to respond to treatment. Desmoid tumours undergo an unpredictable and variable trajectory where some tumours grow aggressively while others remain unchanged for long periods of time or spontaneously shrink. There are currently no good tests to predict which patients are likely to go on to have aggressive or indolent forms of the disease. Our research is aimed at discovering the matrisomal components that drive aggressiveness in desmoid tumours and develop biomarkers for predicting tumour outcomes. In this project, we will employ protein profiling of desmoid tumour specimens to establish which components of the matrisome are enriched in patients with aggressive tumours. Once identified, these molecular components will be assessed for their ability to predict the clinical course of desmoid tumours and in doing so, allow us to study the complex biological processes that regulate tumour growth. Our ultimate goals are to develop new ways of identifying which patients are most likely to harbour aggressive tumours and how best to treat these patients. If successful, our work will provide the basis for new clinical trials that will help doctors to personalise treatment of individual desmoid tumour patients whilst providing important new insights into the molecular drivers of tumour growth in this disease.
Scientific Abstract
Desmoid tumours are characterised by an unpredictable and variable natural history with periods of tumour growth, stable disease and even spontaneous regression. While genomic analyses of desmoid tumours have deepened our understanding of the molecular pathology of the disease, there remains a large gap in translating this knowledge into robust prognostic biomarkers and effective treatments. In contrast to the tumour cell compartment, the biology of the tumour microenvironment in desmoid tumours, specifically the microenvironmental component comprising the extracellular matrix and associated proteins (collectively known as the matrisome), remains largely unknown. Notably, the matrisome has been shown in other cancer types to be a rich source of therapeutic targets and prognostic biomarkers. The objective of this proposal is to harness the power of proteomics to characterise, in unprecedented detail, the desmoid tumour matrisome in clinical specimens from both aggressive and indolent forms of the disease. By defining the dynamic matrisomal remodelling associated with aggressive tumours, our novel approach seeks to identify prognostic biomarkers for the prospective stratification of patients with tumours that are likely to follow an indolent versus an aggressive course, as well as candidate drug targets and therapies for this disease. We anticipate that this research will ultimately lead to the discovery of innovative biomarkers and therapies to achieve the goal of improved clinical management of these patients.
