Metabolic and Immunological Implications of MME+CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities

作者：Bin Wang, Yue Pan, Yongjie Xie, Cong Wang, Yinli Yang, Haiyan Sun, Zhuchen Yan, Yameng Cui, Ling Li, Yaoyao Zhou, Weishuai Liu, Zhanyu Pan · 发表于：Biological Procedures Online · 年份：2024 · DOI：10.1186/s12575-024-00254-1 · 被引用次数：11 · 研究领域：Cancer, Hypoxia, and Metabolism、Epigenetics and DNA Methylation、Pancreatic and Hepatic Oncology Research

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 tr...