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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TRAIN (Tribbles Research and Innovation Network)

Teaser

Summary

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.

Work performed

The TRAIN Programme set out to define a more effective approach to the study of the causes and clinical consequences of obesity-related metabolic disease, with a specific focus on aggressive prostate cancer (PCa). Our experimental approaches are centred around manipulation of Tribbles genes, as this family of pseudokinases have previously been shown to play a critical role in processes underpinning the development of these pathologies.

This Programme integrates the work of 10 Beneficiaries and a number of Partners, many of whom have not previously collaborated with each other. Thus, many of the early activities focussed on creating a flourishing, highly collaborative network of participants, including the supervisors, early stage researcher (ESR) trainees and other individuals and institutions affiliated with TRAIN. Establishment of regular journal clubs and progress meetings for the ESRs led not only to an in-dept understanding of every project but was also critical for the development of shared reagents that have been thoroughly validated, thus providing a common platform for highly synergistic research.

The main activities have included:
(i) In-house training courses at individual Beneficiaryâ€™s centres â€“ a wide range of complementary skills training and knowledge development.
(ii) Skills and specific methodology training sessions during the TRAIN workshops (e.g. next generation sequencing/bioinformatics, academic writing, statistics).
(iii) Hosting several seminar speakers at the first two TRAIN Workshops.
(iv) High PI attendance at the TRAIN workshop with discussions on scientific progress.
(v) A regular, formal student-led Journal Club.
(vi) ESRs presenting (poster and oral) their work at several national and international symposia.

Final results

Focus to-date has been on developing/validating tools and models (in vitro and in vivo) of tissue-specific alterations of immune cell function and dysfunctional adipose, combined with cutting edge models of PCa development that enable specific scientific questions to be addressed for the first time. In outline, consortium participants have jointly developed a range of inter-connected tissue-specific models to ascertain the contributions of Tribbles-mediated activities in cell types most critical for the well-being (or otherwise) of the peri-prostatic micro-environment during both the initiation and progression of PCa.

The analysis of these models in now well under-way and our regular forums are being used to co-ordinate activities, thereby ensuring maximal synergy. There is also a coordinated effort to characterise Tribbles-mediated/dependent functional features in a range of human PCa cell lines, as well as non-malignant controls. Combined findings from in vivo models, human cell lines and human samples are increasingly being used to test specific hypotheses, an approach which is envisaged to rapidly lead to several joint scientific outputs.
Network-wide training of the ESRs within this highly collaborative international environment promises to realise a highly connected and highly skilled cohort of expertise with the connections and knowledge-base to advance the translation of basic scientific research into improved therapies for many years to come.