成纤维细胞代谢亚型的鉴定及通过CREB3L1调控其糖酵解促进胰腺癌侵袭转移的作用机制

胰腺癌微环境中的CAF具有异质性，可被分为功能不同的数个亚群。目前代谢相关的CAF亚群尚未见报道。申请人前期通过单细胞测序发现胰腺癌微环境中一类新的CAF亚群，具有较强的糖酵解能力，该CAF亚群的数量与胰腺癌的复发转移及总生存相关。申请人进一步分析显示：转录因子CREB3L1可能是调控该群CAF代谢重编程的关键分子，其具体机制尚不明确。因此，申请人提出科学假说如下：胰腺癌微环境中存在代谢相关的CAF亚群-meCAF， CREB3L1调控meCAF代谢重编程促进其糖酵解从而增强胰腺癌的侵袭转移能力。该项目拟在体外分离并鉴定该类CAF亚群，利用共培养模型及动物模型，探索CREB3L1对该类CAF亚群糖酵解的调控机制及对胰腺癌侵袭转移能力的影响，并在临床样本中进一步验证。本课题的研究，将阐明将阐明胰腺癌微环境中该类CAF亚群通过糖酵解促进胰腺癌侵袭转移的机制，为胰腺癌治疗提供新的靶点及思路。

CAFs in the microenvironment of pancreatic cancer are heterogeneous and can be divided into several subgroups with different functions. At present, there is no report on the metabolism related CAF subgroup. We first identified a new subtype of CAF (metabolically activated CAF, meCAF) in the microenvironment of pancreatic cancer through single cell sequencing. Compared with other subgroups, it has a stronger glycolytic capacity. The number of CAF subgroups was correlated with the recurrence of pancreatic cancer and overall survival. Our further analysis showed that the transcription factor CREB3L1 may play a key role in regulating the metabolic reprogramming of meCAF, and the specific mechanism is not yet clear. Therefore, we proposes a scientific hypothesis as follows: there is a metabolic CAF subgroup-meCAF in the pancreatic cancer microenvironment, and CREB3L1 regulates meCAF metabolic reprogramming and promote its glycolysis to enhance the invasion and metastatic ability of pancreatic cancer. The project intends to isolate and identify this type of CAF subgroup in vitro, using co-culture models and animal models to explore the regulatory mechanism of CREB3L1 on the glycolysis of meCAF. This research will clarify the mechanism of meCAF promoting invasion and metastasis of pancreatic cancer through enhanced glycolysis in pancreatic cancer microenvironment, and provide new targets and ideas for the treatment of pancreatic cancer.