Obesity is associated with a number of chronic diseases that reduce life expectancy, including cardiovascular disease (CVD), type 2 diabetes and several common cancers yet obesity levels continue to grow steadily in both industrialized and emerging economies. If this trend is not reversed, it is predicted that obesity-related diseases will rank among the biggest causes of premature death. Indeed, the global importance of this issue is reflected in the current EU Health Policy, which addresses both health risk mitigation around (unhealthy) diet and tackling chronic diseases as part of the Healthy Ageing agenda.
In the EU, aggressive prostate cancer (PCa) exhibits the highest incidence among cancer types in men and is the third most common cause of cancer death5. The first stage of this oncological condition, also termed prostate intraepithelial neoplasia (PIN), arises from aberrant proliferation of epithelial cells, which can alter the structure of the gland leading to the loss of basal membrane structure and production of invasive PCa lesions. Invasive PCa frequently acquires androgen-independent features and metastatic potential, accounting for a large fraction of observed morbidity and mortality. Improving PCa diagnosis and treatment is a recognised priority in H2020 funded projects
Immunometabolism and its interface(s) with obesity-associated cancers remains a neglected area. Traditionally, academic researchers have tended to focus on specific aspects of immunometabolism, for example: the activities of adipose tissue (AT)-resident macrophages in obesity; the metabolic control of T-cell differentiation; differences in immune cell and adipocyte numbers in AT samples from lean and obese individuals; and the association between obesity and aggressive prostate cancer. However, adopting this approach in isolation from the talent of industry and other key stakeholders has precluded an in-depth and mechanistic understanding of the consequences of obesity and dysfunctional AT on the onset and progression of multiple, seemingly unrelated cellular pathologies, for example, CVD, breast cancer and aggressive PCa. Our Tribbles Research and Innovation Network (TRAIN) will address these shortcomings by providing novel insights into the immuno-metabolic regulation of PCa, thereby opening the door for new treatment strategies.
TRAIN comprises five Research Objectives, addressed by fifteen Individual ESR Projects:
1. Characterise the roles of TRIB1 and -3 expressed by resident cells (e.g. macrophages, regulatory T-cells (Tregs), iNKT) of adipose-tissue (AT) in regulating the inflammatory status of individual AT depots, including peri-prostatic AT.
2. Determine the roles of adipocyte-specific TRIB1 and -3 expression in regulating adipocyte differentiation, immune cell content and activities of metabolic and peri-prostatic AT plus the systemic changes arising from altered AT compositions and functions, including the impact of diet-induced obesity.
3. Define isoform-specific effects of prostatic epithelial cell TRIB expression on Tribbles-mediated functions and activities (Fig1b), as well as the effects of TRIB1 and -3 on prostate cancer progression, via local and systemic alterations in immuno-metabolism.
4. Analyse/define the mechanisms regulating cell- & isoform-specific TRIB1 &-3-mediated effects on immuno-metabolic profiles in health & disease (e.g. human tissues, mouse models) by genomics and systems biology strategies.
5. Characterise the immuno-metabolic outcomes of altering TRIB activity via cell- and isoform-specific Trib knockout and transgenic mice models, miRNA-mediated regulation of TRIB levels in vitro and by developing inhibitors of TRIB3 degradation.
