Cell type-specific molecular mechanisms by which glucose availability regulates cell mechanics and function

SUMMARY/ABSTRACT The proposed study aims to address the following three critical questions in cell mechanobiology field for better understanding of how cells translate external biochemical cues to regulate their function via modulation of cell mechanics. (1) What are the molecular mechanisms by which extracellular glucose levels alter cell mechanics and functions? Glucose is an essential nutrient for virtually all types of cells including immune cells and epithelial cells to support their survival and proper function. Glucose level varies in local tissues due to differential consumption rate by cells and/or altered interstitial fluid pressure in pathological conditions such as inflammation and cancer. Dynamic rearrangement of actin cytoskeleton is critical for cell physiology. Cells spend 50% of their energy to support actin cytoskeleton rearrangement, which determines cell mechanics and function. Cell mechanotypes include cell shape, deformability, and contractility. We have reported that extracellular glucose level alters cell mechanics and we will further elucidate the underlying molecular mechanisms by which glucose metabolism regulates cell mechanotype changes. (2) How cell mechanics is regulated in spatiotemporal framework? Cell mechanotype alterations span many length scales and timescales. It is intuitive that cell mechanotype changes can happen promptly after triggered by external cues as cytoskeleton remodeling and post-translational modification of myosin activating signaling pathway can happen within seconds to minutes. However, we don't understand how dynamically cell mechanotype changes are regulated over time in subcellular resolution. We are in a unique position to investigate the persistency, reversibility, oscillation, and memorization of altered cell mechanotypes. (3) Are there shared signaling axes or cell type-specific axis to regulate cell mechanics in different cell types? Our published and preliminary data shows that glucose-induced changes in cell mechanics and function are cell type-dependent. M1φ is similar to MCF10A cells, while M0φ and M2φ are similar to MDA-MB-231 cells in terms of their mechanotype changes in response to extracellular glucose level: no significant changes were observed from M1φ and MCF10A, while increased stiffness and contractility were observed from M0φ, M2φ, and MDA-MB-231 cells with high glucose levels. We will investigate the shared or distinct molecular mechanisms by which cell mechanics are regulated. Successful completion of the proposed work will significantly improve our understanding on the effects of extracellular glucose levels on cell mechanics and function. Furthermore, this novel knowledge will serve as a basis of future translational studies utilizing the cell mechanotypes for effective therapeutic options on various diseases including cancer and infectious diseases.