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部位运输脂质，这是维持细胞内脂平衡对人类健康至关重要的过程。事实上，调节细胞器接触部位形成的基因与II型糖尿病、神经退行性疾病和癌症有关。溶酶体在处理和运输来自不同过程的脂类方面起着关键作用，例如自噬。自噬对环境营养状况的反应是维持脂类代谢产物的基础水平，其中溶酶体不仅处理和运送脂类，而且通过控制细胞生长和代谢的主宰mTORC1来调节自噬。然而，构成溶酶体-细胞器接触部位的分子和调节接触动力学的命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，并劫持自噬来重新编程脂质代谢，因此了解溶酶体动力学在信号和自噬中的作用并识别关键分子是非常重要的，这些分子可能成为抗癌的潜在靶点。 这一应用的主要目的是研究在肥胖相关癌症的背景下，溶酶体如何改变其动力学(运动性、定位和接触)以在信号和脂肪运输中发挥作用，以响应过量的环境脂类。中心假说是，在癌症的发展过程中，营养环境的改变改变了溶酶体的动力学，从而通过mTORC1和自噬改变了脂质代谢，这是为癌细胞提供脂质和能量的一种适应性方式。我们最近发现的蛋白质复合体BORC和溶酶体动力学机制的其他组件为研究它们在脂类代谢中的作用提供了前所未有的机会。我的初步结果表明，BORC基因的缺失抑制了肿瘤的生长，并在细胞水平上导致溶酶体中胆固醇的积累和脂滴的减少。进一步的分析表明，BORC调控的HOPS复合体与ER复合体NRZ相互作用，这可能是形成溶酶体-ER接触将胆固醇从溶酶体运输到ER的原因。我将继续这些研究，以揭示溶酶体动力学对脂质运输和信号的调节如何促进癌细胞恶性，并寻找潜在的抗癌药物开发靶点。

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.