Lysosome Dynamics-Regulated Lipid Metabolism in Pancreatic Cancer

越来越多的证据表明，细胞利用细胞器接触位点运输脂质，这是维持细胞脂质稳态对人体健康至关重要的过程。事实上，介导细胞器接触位点形成的基因与II型糖尿病、神经退行性疾病和癌症有关。溶酶体在加工和运输来自不同过程的脂质中起关键作用，如自噬。自噬过程中，溶酶体不仅加工和传递脂质，还通过控制细胞生长和代谢的主子mTORC1来调节自噬过程，从而维持脂质代谢产物的基础水平。然而，构建溶酶体-细胞器接触位点的分子和调节接触动力学的指令信号在很大程度上仍然未知。癌细胞具有异常的营养环境，表现出不同的溶酶体动力学，并劫持自噬来重编程脂质代谢，因此了解溶酶体动力学在信号传导和自噬中的作用，并确定关键分子，作为抗癌的潜在靶点具有重要意义。

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.