胰腺癌是一种毁灭性的恶性肿瘤，死亡率高、预后差、治疗选择有限。肿瘤微环境（TME）在肿瘤进展和治疗耐药中起着至关重要的作用。 TME 内的多个癌症相关成纤维细胞 (CAF) 亚群可以在不同状态之间切换，在胰腺癌中表现出抗肿瘤和促肿瘤功能。靶向成纤维细胞相关蛋白和其他基质成分似乎是对抗胰腺癌的一种有吸引力的方法。本研究采用单细胞转录组测序来鉴定胰腺癌中表达 MME（膜金属内肽酶）的 CAF。根据肿瘤分化、淋巴结转移和 T 期参数进行系统筛查，以识别和确认称为 MME CAF 的成纤维细胞亚群的存在。随后的分析包括时间研究、以缺氧信号通路为重点的细胞间通讯模式探索，以及胰腺癌微环境中 MME CAF 功能的研究。通路富集分析和临床相关性揭示了 MME 高表达与糖酵解、缺氧标志物和促癌炎症通路之间的密切关联。 MME CAF 的作用通过体内和体外实验得到验证，包括高通量药物筛选以评估潜在的靶向治疗策略。单细胞转录组测序揭示了具有高 MME 表达的肿瘤相关成纤维细胞，称为 MME CAF，在 TME 中表现出独特的终末期分化功能。 MME CAF 参与缺氧信号通路表明其通过细胞间通讯对胰腺癌进展产生潜在影响。 MME 高表达与胰腺癌患者糖酵解、缺氧标志物 (VEGF) 和促癌炎症途径增加相关，与较低的生存率、晚期疾病阶段和较高的癌基因突变率相关。动物实验证实，CAF 中 MME 表达升高会增加肿瘤负荷，促进免疫抑制微环境，并增强对化疗和免疫治疗的抵抗力。开发的MME CAF抑制剂IOX2（一种特异性脯氨酰羟化酶2（PHD2）抑制剂）与AG（紫杉醇  吉西他滨）和抗PD1疗法相结合，表现出良好的抗肿瘤作用，为靶向胰腺癌CAF中的MME提供了转化策略。研究结果强调了 MM​​E CAF 通过塑造 TME 和影响关键通路在胰腺癌进展中的重要作用。针对 MME 提出了一种对抗该疾病的有前景的策略，对旨在破坏 MME CAF 功能和增强胰腺癌治疗功效的治疗干预具有潜在影响。© 2024。作者。

Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.© 2024. The Author(s).