PO.TB10.13 · 肿瘤生物学
神经营养受体GFRalpha2驱动肝转移中Kupffer细胞的促转移编程
Neurotrophic receptor GFRalpha2 drives pro-metastatic programming of Kupffer cells in liver metastases
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摘要 Abstract
中文摘要
结直肠癌、胃癌和胰腺癌等胃肠道癌症常转移至肝脏，显著促成癌症相关死亡率和对免疫检查点抑制剂（ICIs）的耐药。近期多学科研究强调了癌症中神经系统与免疫系统之间的功能性和机制性相互作用，称为神经免疫轴。鉴于肝脏丰富的神经支配，我们通过利用来自结直肠癌肝转移（CRLM）患者的单细胞组学数据集分析217种已知参与传出信号传递的受体的表达谱，研究神经免疫信号是否促成肝转移，其中胶质细胞源性神经营养因子（GDNF）家族受体alpha 2（GFRalpha2）因其在CRLM邻近肝脏中相对于来自移植供体的健康肝脏可重复且专一性升高的表达而被鉴定。我们利用scRNA-seq、高维流式细胞术和多重免疫荧光分析在小鼠和CRLM患者中进一步证实GFRalpha2在Kupffer细胞（KCs）上选择性表达并上调。值得注意的是，GFRalpha2 + KCs在CRLM中位于肝脏浸润神经纤维附近，而化学性肝去神经导致GFRalpha2表达减少，提示GFRalpha2 + KCs可能受神经调控。功能上，慢病毒shRNA介导的Gfra2敲低显著抑制肝转移而不影响原发结直肠肿瘤生长，且此效应可被脂质体氯膦酸盐清除KCs所消除。机制上，GFRalpha2 + KCs表现出受损的抗原呈递能力，但增强的促血管生成和中性粒细胞募集，提示一种重编程的、促转移的表型。值得注意的是，Gfra2敲低显著减少中性粒细胞积聚和血管生成，但增加MHCII + KCs。综上，我们的发现指出GFRalpha2上调将KCs重编程为促转移状态，从而促进肝转移。
查看英文原文 English abstract
Gastrointestinal cancers such as colorectal, gastric and pancreatic cancers frequently metastasize to the liver, contributing significantly to cancer-related mortality and resistance to immune checkpoint inhibitors (ICIs). Recent multidisciplinary studies have highlighted a functional and mechanistic interplay between the nervous and immune systems in cancers, termed as neuroimmune axis. Given the rich hepatic innervation, we investigated whether neuroimmune signaling contributes to liver metastasis by analyzing the expression profiles of 217 known receptors involved in efferent signal transmission using single-cell omics datasets from colorectal cancer liver metastasis (CRLM) patients, among which glial cell line-derived neurotrophic factor (GDNF) family receptor alpha 2 (GFRalpha2) was identified due to its reproducibly and exclusively elevated expression on CRLM adjacent livers compared with healthy livers from transplantation donors. Using scRNA-seq, high-dimensional flow cytometry and multiplex-immunofluorescence analysis in mice and patients with CRLM, we further confirmed that GFRalpha2 was selectively expressed and upregulated on Kupffer cells (KCs). Notably, GFRalpha2 + KCs were found in close proximity to liver-infiltrating nerve fibers in CRLM, whereas chemical liver denervation led to reduced expression of GFRalpha2, suggesting a possible neural regulation on GFRalpha2 + KCs. Functionally, lentiviral shRNA-mediated Gfra2 knockdown significantly suppressed liver metastasis without affecting primary colorectal tumor growth, which could be abolished by KCs depletion using liposomal clodronate. Mechanistically, GFRalpha2 + KCs displayed impaired antigen presentation capacity, but enhanced pro-angiogenesis and neutrophil recruitment, suggesting a reprogrammed, metastasis-promoting phenotype. Notably, Gfra2 knockdown significantly reduced neutrophil accumulation and angiogenesis, but increased MHCII + KCs. Taken together, our findings pinpointed that GFRalpha2 upregulation reprograms KCs towards a pro-metastatic state, thereby facilitate liver metastasis.
利益披露 Disclosure
J. Chen, None..
J. Zhou, None.