ABSTRACT

KRAS is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand the effects of KRAS mutation in cancer cells, the direct effects of the oncogenetic KRAS activation on immune cells remain elusive. Here, we report that extracellular KRAS^G12D is essential for pancreatic tumor-associated macrophage polarization. Oxidative stress induces KRAS^G12D protein release from cancer cells succumbing to autophagy-dependent ferroptosis. Extracellular KRAS^G12D packaged into exosomes then is taken up by macrophages through an AGER-dependent mechanism. KRAS^G12D causes macrophages to switch to an M2-like pro-tumor phenotype via STAT3-dependent fatty acid oxidation. Consequently, the disruption of KRAS^G12D release and uptake can abolish the macrophage-mediated stimulation of pancreatic adenocarcinomas in mouse models. Importantly, the level of KRAS^G12D expression in macrophages correlates with poor survival in pancreatic cancer patients. These findings not only identify extracellular KRAS^G12D as a key mediator of cancer cell-macrophage communication, but also provide a novel KRAS-targeted anticancer strategy.

Abbreviations: DAMP, damage-associated molecular pattern; PBMCMs, peripheral blood mononuclear cell-derived macrophages; PDAC, pancreatic ductal adenocarcinoma; s.c., subcutaneously; TAMs, tumor-associated macrophages; TME, tumor microenvironment.

摘要

KRAS是人类肿瘤中最常见突变的癌基因。尽管投入了大量资金来了解 KRAS 突变对癌细胞的影响，但致癌 KRAS 激活对免疫细胞的直接影响仍然难以捉摸。在此，我们报告细胞外 KRAS ^G12D对于胰腺肿瘤相关巨噬细胞极化至关重要。氧化应激诱导癌细胞释放KRAS ^{G12D蛋白，导致自噬依赖性铁死亡。}细胞外 KRAS ^G12D包装到外泌体中，然后通过 AGER 依赖性机制被巨噬细胞摄取。KRAS ^G12D通过 STAT3 依赖性脂肪酸氧化导致巨噬细胞转变为 M2 样促肿瘤表型。因此，破坏 KRAS ^G12D的释放和摄取可以消除小鼠模型中巨噬细胞介导的胰腺腺癌刺激。^{重要的是，巨噬细胞中 KRAS G12D}的表达水平与胰腺癌患者的较差生存率相关。这些发现不仅确定了细胞外 KRAS ^G12D是癌细胞-巨噬细胞通讯的关键介质，而且还提供了一种新的 KRAS 靶向抗癌策略。

缩写： DAMP，损伤相关分子模式；PBMCM，外周血单核细胞来源的巨噬细胞；PDAC，胰腺导管腺癌；sc，皮下注射；TAM，肿瘤相关巨噬细胞；TME，肿瘤微环境。