Cong Fei, Bao Hongcun, Wang Xianfeng, Tang Yang, Bao Yuwei, Poulton John S, Liu Xiaowen, Wong Adam Chun-Nin, Ji Xiang, Deng Wu-Min
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA.
Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
EMBO J. 2025 May 22. doi: 10.1038/s44318-025-00458-5.
Paraneoplastic syndrome represents severe and complex systemic clinical symptoms manifesting in multiple organs of cancer patients, but its cause and cellular underpinnings remain little explored. In this study, establishing a Drosophila model of paraneoplastic syndrome triggered by tumor transplantation, we found that the innate immune response, initiated by translocated commensal bacteria from a compromised intestine, significantly contributes to reduced lifespan in tumor-bearing hosts. Our data identify the renal system as a central hub of this paraneoplastic syndrome model, wherein the pericardial nephrocytes undergo severe damage due to an elevated immune response triggered by gut dysbiosis and bacterial translocation. This innate immune response-induced nephrocyte damage is a major contributor to reduced longevity in tumor-bearing hosts, as blocking the NF-kB/Imd pathway in nephrocytes or removing gut bacteria via germ-free derivation or antibiotic treatment ameliorates nephrocyte deterioration and extends the lifespan of tumor-bearing flies. Consistently, treatment with a detoxifying drug also extended the lifespan of the tumor hosts. Our findings highlight a critical role of the gut-kidney axis in the paraneoplastic complications observed in cancer-bearing flies, suggesting potential therapeutic targets for mitigating similar complications in cancer patients.
副肿瘤综合征表现为癌症患者多个器官出现的严重且复杂的全身临床症状，但其病因和细胞基础仍鲜为人知。在本研究中，通过建立肿瘤移植引发的副肿瘤综合征果蝇模型，我们发现，来自受损肠道的共生细菌移位引发的先天免疫反应，显著导致荷瘤宿主寿命缩短。我们的数据确定肾脏系统是该副肿瘤综合征模型的核心枢纽，其中心包肾细胞因肠道菌群失调和细菌移位引发的免疫反应增强而受到严重损伤。这种先天免疫反应诱导的肾细胞损伤是荷瘤宿主寿命缩短的主要原因，因为阻断肾细胞中的NF-κB/Imd途径或通过无菌衍生或抗生素治疗去除肠道细菌可改善肾细胞恶化并延长荷瘤果蝇的寿命。同样，使用解毒药物治疗也可延长肿瘤宿主的寿命。我们的研究结果突出了肠道-肾脏轴在荷瘤果蝇中观察到的副肿瘤并发症中的关键作用，提示了减轻癌症患者类似并发症的潜在治疗靶点。
