For this study, the Cancer Biology and Therapeutics group (Prof. Gallagher and Prof. Brennan, www.cbtlab.ie ) will combine with Prof. LeRoux?s group to investigate the molecular basis of obesity-related carcinogenesis.
The main focus of this study will be endometrial cancer (EC). Obesity is a major risk factor for EC and together with Australian Collaborators, we are performing a trial of weight loss as a treatment for early-stage EC. The FeMMe trial, which will complete recruitment in 2017, will provide an extensive biobank to help elucidate the relationship between weight loss, metabolic control and EC biology.
Prof. Brennan has extensive experience in elucidating inflammatory responses in the tumour microenvironment which plays a major role in obesity-related cancers(1). Prof. Gallagher has an exceptional record in directing large-scale cancer research programmes, with a particular emphasis on the application of high-throughput ?omics? approaches and in vivo imaging(2) while Prof. LeRoux is a world leader in obesity treatment(3) and the development of animal models of metabolic surgery(4).
1. DENARDO et al. Cancer Discovery 2011
2. MICHAUT et al.. Sci Rep 2016.
3. PI-SUNYER X et al. N Engl J Med 2015
4. ABEGG K, Am J Physiol Regul Integr Comp Physiol 2015
Individuals with central obesity, metabolic syndrome and/or diabetes are at significantly increased risk of endometrial cancer. Metabolic surgery has demonstrated a 30% reduction in cancer risk, with this effect only seen in females. Our pilot data demonstrate that the obesity-related local inflammatory milleu promotes cancer progression. Herein , we will use in vitro assays, animal models and human serum/tissue samples from the FeMMe trial to investigate this relationship in more detail.
We have optimised in vitro assays to investigate the cellular response to obesity and/or the metabolic syndrome. Using co-culture models, we will use existing endometrial cancer cell lines and primary endometrial cell cultures to examine the phenotypic changes induced by adipose tissue from lean and obese individuals. We will also perform next generation sequencing (NGS) experiments on these cell lines following co-culture, with these in vitro models also being used throughout the study for downstream functional validation of our findings.
The second part of the project will focus on the BDII/Han rat model in which 90% of virgin females develop endometrial cancer by 24 months. Using a high fat diet to induce obesity, we will perform a randomised study of vertical sleeve gastrectomy versus a sham laparotomy to assess the effect of 20% intentional weight loss on endometrial cancer development and metastases. Tumour development will be monitored using microPET/CT imaging and endometrial cancers will be harvested at the study endpoint for NGS experiments to provide a global assessment of the effect of intentional weight loss on endometrial cancer biology.
The final part of the study will be combine the NGS data from the in vitro and animal models to identify key pathways in obesity-related endometrial cancer, which will be validated in patient samples from the prospective FeMME trial using immunohistochemistry, gene expression studies and serum analysis.