代谢应激因子乳酸诱导胰腺星状细胞自噬在胰腺癌微环境重塑中作用及机制

胰腺星状细胞（PSC）自噬为胰腺癌微环境重塑的关键节点，其机制尚不明确。胰腺癌代谢重编程以及乏血管特性导致微环境乳酸大量堆积。课题组发现高浓度乳酸诱导静息PSC自噬并转为活化表型，促进共培养胰腺癌细胞增殖与侵袭；此外，单羧酸转运蛋白1（MCT1）特异性介导乳酸向PSC胞内转运并活化ERK。有研究表明ERK调控自噬抑制因子mTOR促进自噬。由此设想，乳酸作为代谢应激因子通过MCT1/ERK/mTOR信号轴诱导PSC自噬并活化，重塑胰腺癌微环境。拟采用不同浓度乳酸培养PSC，探讨乳酸诱导PSC自噬的分子机制；进而调控上述信号轴，探讨乳酸诱导PSC自噬对胰腺癌微环境重塑的作用。本研究以活化PSC在微环境重塑的关键作用为切入点，从代谢应激的角度，探讨乳酸诱导PSC自噬在胰腺癌发生发展中作用及机制，为胰腺癌防治研究提供新思路与新靶点，并有助于深入理解代谢重编程-微环境重塑对话在肿瘤发生发展中作用。

The autophagy of pancreatic stellate cell (PSC) is the key point of microenvironment reprogram in pancreatic cancer, but the precise mechanism is undefined. Because of the metabolic reprogram and hypovascularity of pancreatic cancer, amount of lactate is deposited in the extracellular microenvironment. Our previous study showed that high concentration lactate can induce activation and autophagy of PSC, which enhancing the proliferation and invasion of pancreatic cancer cells. Meanwhile, the results demonstrated that the lactate was specifically transferred into PSC by MCT1 and continually activated ERK signal, which was verified to enhance autophagy by regulating mTOR/Beclin pathway. Therefore, we hypothesize that lactate functions as metabolic stress factor and induces autophagy and activation of PSC via MCT1/ERK/mTOR/Beclin1 signal pathway, which further promotes microenvironment remodeling and development of pancreatic cancer. In this study, the PSCs were treated with lactate in different concentration to investigate the mechanism of lactate-induced autophagy and activation of PSC. Furthermore, the MCT1/ERK/mTOR/Beclin1 axis is regulated to evaluate the effects of lactate-induced autophagy and activation of PSC on microenvironment remodeling and development of pancreatic cancer. The present study concentrates on the key function of activated PSCs in microenvironment remodeling of pancreatic cancer, and from the perspective to metabolic stress, to explore the function of lactated-induced PSC autophagy in the tumorigenesis of pancreatic cancer. The study affords a novel strategy and target for therapeutic of pancreatic cancer, and gives deep insight in the crosstalk between metabolism reprogram and microenvironment remodeling in tumorigenesis.