Hungry Tissues: Mechanical-metabolic coupling in tissue formation and tumour initiation

Cells are the building blocks of tissues, and their behaviours, such as growth, movement, and organisation, determine how tissues form, repair, and maintain function. Disruptions in these behaviours contribute to diseases including cancer, fibrosis, and degenerative disorders. Two key processes strongly influence cell behaviour: tissue mechanics, which governs how cells generate and respond to forces, and metabolism, which provides energy and the building blocks for growth. Although often studied separately, mechanics and metabolism are intimately linked. Forces influence energy production, while metabolic state affects how cells generate and transmit forces. This interplay, called mechanical–metabolic coupling, is poorly understood, limiting our ability to prevent or treat disease.

This fellowship aims to define the mechanisms and consequences of mechanical–metabolic coupling, using mammary epithelial cells as a model. Breast tissue undergoes repeated growth and remodelling, making it ideal to study how mechanical and metabolic signals interact. Breast cancer is a major cause of death in the UK, and any insights that prevent disease initiation would have important societal impact. High mammographic density, reflecting altered tissue mechanics, is a major risk factor, while metabolic reprogramming contributes to disease progression and influences treatment outcomes. Understanding how these signals cooperate or conflict will reveal early vulnerabilities that can be targeted for disease prevention, particularly in high-risk individuals.

The project has three main aims. First, I will identify molecular regulators that integrate mechanical and metabolic signals, focusing on proteins that connect the cell’s structural framework (cytoskeleton) and force generation to energy use. By systematically manipulating these regulators and measuring forces, metabolism, and cell behaviour, I will uncover how cells balance these inputs to maintain tissue function. Second, I will determine how this coupling controls collective cell behaviours that drive tissue dynamics, such as growth, migration, and organisation. Using live-cell imaging and advanced computational models, I will map how mechanical and metabolic signals coordinate across individual cells to produce tissue-level behaviours. Third, I will explore how mechanical–metabolic coupling contributes to the earliest stages of tumour formation. Using genetically distinct human mammary epithelial cells, I will measure how combinations of mechanical and metabolic cues influence proliferation, invasion, and tissue organisation, and identify regulators that could be targeted to prevent tumour initiation.

The potential applications of this work extend beyond breast cancer. By defining principles of mechanical–metabolic integration, it will inform strategies to manipulate tissue dynamics in regenerative medicine, tissue engineering, and fibrosis. Findings will provide a framework for developing early interventions in high-risk patients and for designing engineered tissues that self-organise, repair, and resist disease. I will also engage patients and the public using 3D-printed tissue models and explanatory tools, illustrating how fundamental research translates into health benefits.

Overall, this fellowship will establish mechanical–metabolic coupling as a central principle of tissue biology, revealing how physical and metabolic cues jointly control cell behaviour, tissue organisation, and disease initiation. By integrating molecular, cellular, and computational approaches, it will deliver insights with broad scientific, clinical, and societal impact.