Glycolytic metabolism is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and tumor-associated stromal cells play important roles in tumor metabolism. We previously reported that tumor-associated macrophages (TAMs) facilitate PDAC progression. However, little is known about whether TAMs are involved in regulating glycolysis in PDAC. Here, we found a positive correlation between CD68 TAM infiltration and FDG maximal standardized uptake (FDG SUVmax) on PET-CT images of PDAC. We discovered that the glycolytic gene set was prominently enriched in the high TAM infiltration group through Gene Set Enrichment Analysis using The Cancer Genome Atlas database. Mechanistically, TAMs secreted IL-8 to promote GLUT3 expression in PDAC cells, enhancing tumor glycolysis both in vitro and in vivo, whereas this effect could be blocked by the IL-8 receptor inhibitor reparixin. Furthermore, IL-8 promoted the translocation of phosphorylated STAT3 into the nucleus to activate the GLUT3 promoter. Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

中文翻译：

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胰腺癌进展中肿瘤相关巨噬细胞通过 IL-8/STAT3/GLUT3 信号通路驱动糖酵解

糖酵解代谢是胰腺导管腺癌（PDAC）的标志，肿瘤相关基质细胞在肿瘤代谢中发挥重要作用。我们之前报道过肿瘤相关巨噬细胞 (TAM) 促进 PDAC 进展。然而，关于 TAM 是否参与调节 PDAC 糖酵解尚不清楚。在这里，我们在 PDAC 的 PET-CT 图像上发现 CD68 TAM 浸润与 FDG 最大标准化摄取 (FDG SUVmax) 之间呈正相关。通过使用癌症基因组图谱数据库进行基因集富集分析，我们发现糖酵解基因集在高 TAM 浸润组中显着富集。从机制上讲，TAM 分泌 IL-8 促进 PDAC 细胞中 GLUT3 的表达，从而在体外和体内增强肿瘤糖酵解，而这种作用可以被 IL-8 受体抑制剂 reparix 阻断。此外，IL-8促进磷酸化STAT3易位到细胞核中以激活GLUT3启动子。总体而言，我们证明 TAM 通过 IL-8/STAT3/GLUT3 信号通路促进 PDAC 细胞糖酵解。我们的累积研究结果表明，Reparix 消除 TAM 诱导的肿瘤糖酵解可能表现出抗肿瘤作用，并为 PDAC 提供潜在的治疗靶点。