Kirsty Spalding

Obesity associated diseases, such as type 2 diabetes, are increasing globally at an epidemic rate and we are in dire need of a better understanding of disease pathogenesis and the development of novel treatment strategies. We recently reported that in obesity a subset of cells in human fat tissue senesce, which is a form of premature aging whereby the functioning and secretions of the cell change. Inflammatory factors secreted by senescent fat cells may contribute to local and whole-body inflammation. Given the strong association between fat tissue senescence, type 2 diabetes and metabolic disease, novel therapies aimed at reducing senescent cell buildup are of significant interest. This project will elucidate the role of obesity-associated DNA damage as a driving factor in promoting fat cell senescence and fat tissue inflammation. Important proof of concept validation, elucidating whether a small molecule approach can reduce fat cell senescence and inflammation, will be conducted._x000D_

Excess adipose tissue has been shown to increase the risk for many types of cancers and is associated with poor cancer outcomes. Obesity is increasing in epidemic proportions world-wide, with a concommitttant increase in obesity-associated cancer. Cancers not associated with overweight and obesity, however, are decreasing (US Cancer Statistics, 2017). It is therefore essential to better understand the mechanisms whereby human fat cells contribute to cancer progression. Adipocytes within the tumour microenvironment have been shown to promote cancer progression, however little is known about the contribution of adipose tissue distal to the tumour site. With approximately 90% of the body’s fat being subcutaneous and metastasis a systemic disease, the contribution of this fat depot, in lean and obese states, is of prime importance. This proposal uses technologies recently developed in the Spalding lab to better understand the unique contribution of human fat cellls to cancer metastasis. We recently show that a subset of adipocytes in human adipose tissue senesce and secrete factors known to promote inflammation. This proposal will investigate whether this sub-population of senescent fat cells, which increase in number in obese and hyperinsulinemic individuals, secrete factors which promote a metastatic phenotype (as indicated in unpublished data). Targeting this population of fat cells, to mitigate the adverse effects of obesity on cancer progression, will be investigated.