PhD Studentship: A Bioengineered 3D Model of Obesity-related Breast Cancer to Investigate the Anti-tumour Immune Response Induced by Exercise

Background: Breast cancer diagnoses affect 1 in 7 UK women, estimated to coast ~£3.6 billion by 2034 (breastcancernow.org). Lifestyle factors, including sedentary behaviour and obesity, significantly influence breast cancer risk, with inactivity alone costing ~£7.4 billion/year (www.gov.uk/phe). Secondary metastases cause over two thirds of cancer-related deaths (Dillekas et al., 2019) due to developing chemoresistance driven by cancer stem cells (CSCs; Ramos et al., 2021). Obesity increases breast cancer risk since adipose tissue produces oestrogen and inflammatory cytokines, driving tumour growth (Brown et al., 2012). Exercise combats this by reducing adiposity, but the interplay with CSC function remains unknown. To date, no studies have examined the effects of exercise on CSCs; however, links between obesity and CSC expansion (Picon-Ruiz et al., 2017) suggest exercise will mitigate CSC-driven breast cancer progression.

Most cellular/molecular oncology investigations use 2D cell culture or animal models, which are mandatory in clinical trials of new drugs. However, these models are not physiologically relevant and fail to give consistent results, with 90% of new drugs failing at this hurdle (Sun et al., 2022). Studies in mice display wide variability in results: some show exercise enhances tumour growth (Faustino-Rocha et al., 2016), whilst others demonstrate attenuation of tumour growth and invasion (Westerlind et al., 2003). By contrast, in vitro studies show exercise consistently reduces proliferation, migration and invasion of breast cancer cells (Brown et al., 2021). Moreover, reproducible 3D models can accurately represent complex tissue structures (Xie et al., 2024).

Aims: Our core aim is to investigate relationships between exercise, adiposity and breast cancer in an in vitro model to establish mechanisms for exercise-as-medicine. Our ambition to create a model of obesogenic breast cancer will build on our published model of exercise attenuating breast cancer invasion (Brown et al., 2023). We will develop a multicellular 3D model of obesogenic breast cancer using patient-derived tumour organoids (PDXOs) from the Human Cancer Models Initiative (HCMI) alongside adipocytes. We will then conduct a 12-week moderate intensity exercise training intervention in a cohort of healthy pre- and post-menopausal women of varying BMIs, collecting NK cells and serum to understand the molecular-level protective effects of exercise on these obesogenic PDXOs (obPDXOs) and evaluate CSC status by flow cytometry and immunocytochemistry. Finally, using samples collected before/after exercise training, obPDXOs will be cultured with/without exercised serum (to examine effects on cell growth) or with/without NK cells (to examine anti-tumour immune responses), comparing our results with published findings in both 2D assays and mouse models to benchmark their validity.

Primary supervisor: Dr Mhairi A Morris

Entry requirements:

2:1 undergraduate Bachelors in a biological science-related subject

English language requirements:

Applicants must meet the minimum English language requirements. Further details are available on the International website (http://www.lboro.ac.uk/international/applicants/english/).

Funding information:

The studentship is for three years and provides a tax-free stipend of £19,237 per annum for the duration of the studentship plus university tuition fees.

How to apply:

All applications should be made online via the above ‘Apply’ button. Under programme name, select School of Sport, Exercise and Health Sciences. Please quote the advertised reference number: SSEHS/MM25 in your application.

To avoid delays in processing your application, please ensure that you submit the minimum supporting documents.

The following selection criteria will be used by academic schools to help them make a decision on your application.

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