Zhang Yijuan, Recouvreux M Victoria, Jung Michael, Galenkamp Koen M O, Li Yunbo, Zagnitko Olga, Scott David A, Lowy Andrew M, Commisso Cosimo
Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California.
Cancer Discov. 2021 Jul;11(7):1808-1825. doi: 10.1158/2159-8290.CD-20-0119. Epub 2021 Mar 2.
Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs-it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. SIGNIFICANCE: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth..
尽管胰腺导管腺癌（PDAC）细胞暴露于营养匮乏的肿瘤微环境中，但它们可通过巨胞饮作用获取营养，巨胞饮是一种蛋白质清除的内吞形式，其作用是支持癌症代谢。在此，我们提供证据表明巨胞饮作用在胰腺肿瘤基质中也发挥作用。我们发现谷氨酰胺缺乏会触发胰腺癌相关成纤维细胞（CAF）的巨胞饮摄取。从机制上讲，我们解析出基质巨胞饮作用通过增强胞质钙而增强，并依赖于ARHGEF2和CaMKK2-AMPK信号传导。我们阐明巨胞饮作用在CAF中具有双重功能——它作为维持CAF细胞健康和功能的细胞内氨基酸来源，并且提供促进肿瘤细胞存活的分泌型氨基酸。重要的是，我们证明基质巨胞饮作用支持PDAC肿瘤生长。这些结果突出了巨胞饮作用在肿瘤基质中的功能作用，并提供了关于营养缺乏如何控制基质蛋白清除的机制理解。意义：谷氨酰胺剥夺驱动基质巨胞饮作用以支持CAF细胞健康，并提供维持PDAC细胞存活的氨基酸。选择性破坏CAF中的巨胞饮作用可抑制PDAC肿瘤生长。
