Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer [scRNA-seq]

Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and cancer-associated fibroblasts (CAFs) use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis triggers CAF subtype transitions and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact. Single cell gene expression profiling of KPC orthotopic tumors treated with DMSO or 10 mg/Kg EIPA

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）肿瘤存在谷氨酰胺缺乏的特征，谷氨酰胺是肿瘤细胞与癌相关成纤维细胞（cancer-associated fibroblasts, CAFs）用以维持自身存活与功能适合度的氨基酸。在胰腺导管腺癌中，两类细胞均会激活巨胞饮作用（macropinocytosis），作为应对谷氨酰胺匮乏的适应性应答。癌相关成纤维细胞在塑造肿瘤微环境中发挥关键作用，但细胞对代谢应激的适应性改变如何影响基质结构，目前仍有待阐明。本研究发现，在谷氨酰胺受限的条件下，巨胞饮作用可调控癌相关成纤维细胞的亚型身份。本研究的数据表明，代谢应激会通过MEK/ERK信号通路驱动固有炎性癌相关成纤维细胞（inflammatory CAF, iCAF）程序。借助体内模型，本研究发现阻断巨胞饮作用会触发癌相关成纤维细胞的亚型转换，并重塑肿瘤基质。尤为重要的是，这种基质结构的改变可被用于增强胰腺导管腺癌对免疫治疗与化疗的敏感性。本研究结果证实，代谢应激在肿瘤微环境的塑造中发挥关键作用，且该特性可被转化为临床治疗手段。本研究对经二甲基亚砜（dimethyl sulfoxide, DMSO）或10 mg/kg EIPA处理的KPC原位肿瘤开展了单细胞基因表达谱分析。