Increasing evidence is showing cells use organelle contact sites to transport lipids, which is an essential process to maintain cellular lipid homeostasis for human health. Indeed, the genes mediating formation of organelle contact sites have been linked to type II diabetes, neurodegenerative diseases, and cancer. Lysosomes play a critical role in processing and transporting lipids derived from different processes, such as autophagy. Autophagy maintains the basal level of lipid metabolites in response to environmental nutrient status, in which lysosomes not only process and deliver lipids but also regulate autophagy by controlling mTORC1, the master of cell growth and metabolism. However, the molecules constructing lysosome-organelle contact sites and the commanding signals regulating the contact dynamics are still largely unknown. Cancer cells have abnormal nutrient environments, exhibit different lysosome dynamics, and hijack autophagy to reprogram lipid metabolism, so it is very important to understand the role of lysosome dynamics in signaling and autophagy and identify the key molecules, which could serve as potential targets for anticancer purpose. The main objectives of this application are to study how lysosome change their dynamics (motility, positioning, and contacts) to function in signaling and lipid trafficking in response to excess environmental lipids in the context of obesity-related cancer. The central hypothesis is that during cancer development, altered nutrient environment changes lysosome dynamics and consequently alters lipid metabolism through mTORC1 and autophagy, which serves as an adaptive way to provide lipids and energy for cancer cells. Our recent discovery of the protein complex BORC and other components of the lysosome-dynamics machinery provides unprecedented opportunities to examine their roles in lipid metabolism. My preliminary results indicate deletion of BORC suppressed tumor growth and at cell level caused cholesterol accumulation in lysosomes and reduced lipid droplets. Further analysis revealed BORC-regulated HOPS complex interacted with ER complex NRZ, which is probably responsible for the formation of lysosome-ER contacts to transport cholesterol from lysosomes to ER. I will continue these studies to uncover how the regulation of lipid transport and signaling by lysosome dynamics promotes cancer cell malignancy and look for the potential anticancer targets for drug development.
Cellular mechanical properties, collectively referred to as mechanotype, play a role in cell physiology and pathology, including cell proliferation, survival, metabolism, stem cell differentiation, immune cell migration, and cancer metastasis. Cell deformability and contractility are two key characteristics that determine the mechanotype of a cell. We have focused on understanding how cellular mechanotype is regulated by microenvironmental inputs that have been implicated in cell invasion, such as glucose levels. Hyperglycemia (HG) is prevalent in obesity and diabetes, which in turn are factors facilitating cancer progression.
The effects of HG on cellular mechanotype are the focus of this project. The mentored principal investigator (mPI) has developed a novel cell mechanotyping tool to probe cell deformability, called parallel microfiltration (PMF). In this project, using PMF and related technologies, we will define effects of glucose on cell mechanotype in two distinct model systems: breast cancer cells and macrophages. Our hypothesis is that the HG effects on cellular mechanotype have critical consequences on cell migration, invasiveness, and anoikis. Our long-term objective is to identify pathways that regulate cell mechanotype, migration, and survival under HG conditions, which is of translational relevance and health significance in the context of cancer and immune responses. The specific aims are:
1. Determine how glucose regulates the mechanotype of cancer and immune cells. In this aim, we will define the mechanistic basis of glucose-mediated mechanotype regulation that results in alterations in cell migration. We will use two models: (i) breast cancer cells; and (ii) macrophages. We will employ a novel mechanotyping technique invented by the mPI and collaborators.
2. Delineate how glucose-mediated mechanotype alterations affect cell survival. In this aim, we will determine how regulators and mediators of mechanotype dynamics influence anoikis of cancer cells.