BIO/BME Faculty Search Seminar; Dr. Wenjun Wang

Title: "Mechanometabolism in Tumor Microenvironment"

Abstract: Solid tumors are shaped not only by tumor-intrinsic genetic programs, but also by systemic physiology and the mechanical properties of the tumor microenvironment. In breast cancer, extracellular matrix remodeling is a key regulator of disease progression and therapeutic response, while metabolic disorders such as diabetes and obesity are associated with worse outcomes. Yet mechanics and metabolism are often studied separately, leaving unresolved how systemic metabolic dysfunction remodels tumor mechanics and how mechanical cues regulate cellular metabolism and phenotype across the tumor microenvironment. In this talk, I will first discuss how diabetic hyperglycemia promotes breast tumor progression by reshaping tissue mechanics. Using engineered models and in vivo studies, I showed that diabetic hyperglycemia drives nonenzymatic glycation of the extracellular matrix, which alters matrix mechanics and accelerates disease progression. This remodeling enhances tumor cell proliferation and epithelial-mesenchymal transition, disrupts vascular integrity, and promotes immune suppression, revealing matrix glycation as a mechanistic link between metabolic disease and tumor progression. I will then turn to a second question: how matrix mechanics regulate cell behavior through metabolism. Using engineered hydrogels, quantitative imaging, and metabolic analysis, I found that matrix physical properties impose bioenergetic constraints on endothelial behavior. Collagen density regulates tip -stalk rearrangement during angiogenesis through cellular energetics, while matrix stiffness increases the efficiency with which endothelial cells convert intracellular energy into traction force. Building on this framework, I am now investigating how matrix viscoelasticity regulates T cell metabolism, phenotype, and exhaustion in breast tumors. Together, these studies support a model in which systemic metabolic dysfunction reshapes tissue mechanics, while matrix mechanics regulate cellular energetics and functional state. This work establishes mechanometabolism as a central principle in tumor progression and highlights new opportunities for targeting the tumor microenvironment.