Hungry Acini: How mechanics and metabolism destabilise 3D mammary epithelia during tumour initiation

About the project

About the Project High mammographic density is an important risk factor for breast cancer and is associated with a stiffer mechanical environment around mammary epithelial cells. Increased matrix stiffness can disrupt tissue organisation and alter cellular metabolism, but we do not understand how mechanics and metabolism are coordinated within individual cells as an organised mammary tissue begins to break down. This project will extend an established live-imaging approach for studying mechanical–metabolic coupling in 2D epithelial tissues into 3D mammary acini. Acini reproduce key features of mammary tissue architecture, including epithelial polarity and a central lumen, providing a powerful system in which to investigate the earliest stages of tissue disruption. A central technical goal will be to develop methods for measuring mechanics in and around living 3D acini while simultaneously imaging metabolic activity and tracking cell behaviour. Metabolic biosensors, quantitative microscopy and image analysis will be combined to reveal how these processes are coordinated across space and time in stable acini and as tissue organisation is lost. The student will alter the mechanical and nutritional environment of the acini, including changing matrix stiffness and promoting glycolysis, oxidative phosphorylation or nutrient limitation. These experiments will determine how metabolic responses are coordinated with changes in force generation, cell proliferation, movement and acinar organisation. The project will then test the function of metabolic adaptation during mechanical disruption. By perturbing metabolic pathways identified through the live-imaging experiments, the student will determine whether metabolic adaptation helps acini maintain their organisation under altered mechanical conditions or enables their progression towards disruption. This interdisciplinary project offers training in 3D mammary epithelial culture, metabolic biosensors, mechanobiology, advanced live-cell microscopy and quantitative image analysis. It will reveal how cells coordinate energy metabolism with mechanics to maintain tissue organisation, while providing new insight into how this coordination changes during the earliest stages of tumourigenesis. Eligibility Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in biological sciences, biochemistry, biomedical sciences, cell biology, cancer biology, bioengineering, biophysics or a related subject. Candidates with experience in mammalian cell culture, microscopy, image analysis, biomaterials or quantitative biology are particularly encouraged to apply. Prior experience in every area is not expected. We welcome applicants with a strong interest in interdisciplinary research who are keen to combine experimental cell biology with advanced imaging and quantitative approaches to investigate how mechanics and metabolism shape tissue behaviour. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cell Biology. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

Research areas