Our research programme focuses on understanding the role of proteases in both normal physiology and disease, with a particular emphasis on inflammation and cancer. Proteases tightly control key processes such as immune responses, cell-cycle progression, cell death, tissue remodeling, protein/organelle turnover and metabolic pathway regulation, and their dysregulation is increasingly recognized as a hallmark of many pathologies. This makes them highly attractive targets for innovative diagnostic and therapeutic strategies in oncology.
Cancer cells profoundly rewire their metabolism to sustain rapid growth, survival in hostile conditions and resistance to therapy. They increase uptake of glucose and other nutrients, accelerate glycolysis and reroute its intermediates into biosynthetic and redox-balancing pathways, while converting much of the generated pyruvate to lactate even in the presence of oxygen. This lactate-rich, acidic milieu reshapes the tumour microenvironment, affecting stromal fibroblasts, endothelial cells and immune cells. Glucose transporters GLUT1 and GLUT3 are strongly upregulated in many cancers, enabling cancer cells and tumour-associated macrophages to outcompete other cells for glucose, which correlates with aggressive disease, poor prognosis and altered responses to therapy.
Within this metabolically specialized microenvironment, proteases—particularly lysosomal cathepsins produced by tumour cells and tumour-associated macrophages—are increasingly viewed as potential key regulators at the intersection of metabolism, invasion and immune modulation. Acting on the extracellular matrix, cathepsins promote tumour invasion and metastasis and contribute to angiogenesis by modulating endothelial cells and pericytes, and their high expression associates with poor prognosis and therapy resistance across multiple cancer types.
Understanding how the tumour microenvironment, cancer metabolism and proteases are interconnected is crucial for identifying why some tumours grow, invade and resist therapy more effectively than others. The microenvironment supplies and restricts nutrients, metabolism determines how tumour and immune cells use those nutrients, and proteases remodel the surrounding matrix and signaling landscape in ways that can either support or hinder anti-tumour immunity. By clarifying these links, we can uncover context-specific vulnerabilities and this integrated view offers a path toward more precise diagnostics, better biomarkers of disease progression and more effective, tailored therapies.
The PhD student will explore how changes in nutrient availability shape tumour behaviour and communication between cancer and immune cells, with a particular focus on proteases and the tumour microenvironment. They will use a combination of cell-based models, co-culture systems and mouse tumour models to analyse how metabolic stress influences protease activity, macrophage phenotypes and tumour progression.