代谢异常是肿瘤的重要特征之一。与正常细胞相比，肿瘤细胞即使在有氧条件下也优先使用糖酵解途径，导致胞内大量糖酵解终产物乳酸的生成。肿瘤细胞内过量的乳酸需要及时被释放到细胞外以维持自身pH的稳态和帮助塑造肿瘤微环境。单羧酸转运蛋白4（MCT4）是乳酸向胞外运输的主要转运蛋白。然而，营养状态及肿瘤细胞基因组的改变如何通过MCT4精准调控乳酸向细胞外运输的过程及机制并不明确。本项目的前期研究发现葡萄糖饥饿能够诱导肺癌细胞中MCT4多泛素化并通过蛋白酶体降解。更重要的是，这一过程可能依赖于AMPK介导的MCT4（Ser436）磷酸化。本项目拟以乳酸为切入点，系统研究MCT4在肺癌细胞应对营养状态和基因组改变时进行的乳酸外泌重编程中的功能及其分子机制，并解析LKB1-AMPK-MCT4信号轴在肺癌形成和发展中的作用，为肺癌诊疗提供新的潜在靶点。

Cancer metabolic reprogramming is one of the hallmarks of cancer. Cellular metabolism in cancer cells is consecutively shifted towards the glycolytic pathway together with a decreased dependence on the oxidative pathway, even in the presence of oxygen. Lactate, the end product of glycolysis, is produced excessively by tumor cells and needs to be released outside the cells in time to maintain the steady state of their own pH and help shape the tumor microenvironment. Monocarboxylate transporter 4 (MCT4) is the major protein involved in lactate release. However, the regulation of lactate transportation in cancer cells in response to alterations in tumor microenvironment and genetic features remains elusive. The preliminary experiments of this project found that glucose deprivation induces MCT4 polyubiquitination and proteasomal degradation. More importantly, this process is potentially mediated by phosphorylation of MCT4 at Ser436 by AMPK. In this project, we will employ lung cancer as a model to explore the mechanism of lactate transportation reprogramming in cancer cells upon nutrition deficiencies and genetic alterations, and to elucidate the role of the LKB1-AMPK-MCT4 axis in the formation and development of lung cancer. Considering the importance of cancer cell metabolism, translating the knowledge of lactate transportation reprogramming from this project to the field of cancer metabolism offers new perspectives to therapeutically target cancer, especially lung cancer with LKB1/AMPK alteration.