文章目录

自噬素溶脂信号抑制ccl11 -嗜酸性粒细胞轴促进胰腺癌进展

原文发布日期：2024-01-09

英文摘要：

摘要翻译：

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文章：

自噬素溶脂信号抑制ccl11 -嗜酸性粒细胞轴促进胰腺癌进展

Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression

原文发布日期：2024-01-09

英文摘要：

Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX–LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX–LPA signaling in cancer.

摘要翻译：

脂质及其修饰酶调节肿瘤微环境中的多种特征和癌症进展。分泌的酶自 taxin（ATX）分解外周溶酶体磷脂，生成多功能脂质调节因子溶酶体磷脂酸（LPA），并支持包括胰腺腺癌（PDAC）在内的多种肿瘤的生长。我们发现，ATX抑制了 PDAC 微环境中嗜酸粒细胞的积累。通过基因或药物 ATX 抑制剂的治疗，肿瘤微环境中的嗜酸粒细胞数量增加，这些细胞促进肿瘤细胞局部凋亡并抑制肿瘤进展。机制上，ATX 通过自分泌反馈循环抑制嗜酸粒细胞的积累：ATX-LPA 信号通路负调节 c-Jun（AP-1 转录因子）的活性，从而抑制促嗜酸粒素 CCL11（eotaxin-1）的表达。嗜酸粒细胞在人类 PDAC 标本中被鉴定出来，并且具有肿瘤内部嗜酸粒细胞数量丰富的罕见病例具有最长的总生存期。与最近的研究结果相结合，这项研究揭示了 ATX-LPA 信号通路在癌症中的情境依赖性、免疫调节潜力。