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转运脂质，这是维持细胞内脂质稳态对人类健康的重要过程。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，例如自噬。自噬维持脂质代谢物的基础水平以响应环境营养状态，其中溶酶体不仅处理和递送脂质，而且还通过控制细胞生长和代谢的主人mTORC 1来调节自噬。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命令信号在很大程度上仍然未知。肿瘤细胞具有异常的营养环境，表现出不同的溶酶体动力学，并劫持自噬以重新编程脂质代谢，因此了解溶酶体动力学在信号传导和自噬中的作用并识别可作为抗癌目的的潜在靶点的关键分子是非常重要的。 本申请的主要目的是研究溶酶体如何改变其动力学（运动性、定位和接触）以在肥胖相关癌症的背景下响应于过量环境脂质而在信号传导和脂质运输中起作用。核心假设是，在癌症发展过程中，改变的营养环境改变了溶酶体动力学，从而通过mTORC 1和自噬改变了脂质代谢，这是一种为癌细胞提供脂质和能量的适应性方式。我们最近发现的蛋白质复合物BORC和其他组分的溶酶体动力学机制提供了前所未有的机会，研究他们在脂质代谢中的作用。我的初步结果表明，BORC的缺失抑制肿瘤生长，并在细胞水平上引起胆固醇在溶酶体中的积累和减少脂滴。进一步的分析表明BORC调节的HOPS复合物与ER复合物NRZ相互作用，这可能是负责溶酶体-ER接触的形成，从而将胆固醇从溶酶体转运到ER。我将继续这些研究，以揭示如何通过溶酶体动力学调节脂质转运和信号转导促进癌细胞恶性化，并为药物开发寻找潜在的抗癌靶点。

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.