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Efferocytosis重编程肿瘤微环境促进胰腺癌肝转移

原文发布日期：2024-02-14

英文摘要：

摘要翻译：

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文章：

Efferocytosis重编程肿瘤微环境促进胰腺癌肝转移

Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis

原文发布日期：2024-02-14

英文摘要：

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

摘要翻译：

胰腺导管腺癌是一种高度转移性疾病，巨噬细胞在肝脏转移中起支持作用。胞吞作用（effero cytosus）或巨噬细胞吞并死亡细胞的过程是维持组织 homeostasis 和伤口愈合的关键过程之一，但其在转移中的作用尚不完全明了。本研究发现，在肝转移位点的定居过程中伴随着轻度的组织损伤，而通过胞吞作用清除内)parenchymal死细胞的巨噬细胞重编程及肝脏转移是促进肝转移的关键因素。机制上，巨噬细胞中促粒ausin表达对高效胞吞作用至关重要，该作用受 cystic fibrosis transmembrane conductance regulator 控制的溶酶体酸化和溶酶体 cargo降解控制，进而通过 LXRα/RXRα介导的巨噬细胞转化及arginase 1 表达上调。药物阻断胞吞作用或促粒ausin基因特异性敲除均会削弱巨噬细胞转化能力，改善 CD8+ T 细胞功能并减少肝脏转移。本研究揭示了巨噬细胞在组织修复中硬编码功能如何促进肝转移，并发现了胰腺导管腺癌肝脏转移的潜在靶点。