PO.TB10.15 · 肿瘤生物学
线粒体钙单向转运体通过 NETosis 介导的骨骼肌萎缩驱动胰腺导管腺癌中的癌症恶病质
Mitochondrial calcium uniporter drives cancer cachexia in pancreatic ductal adenocarcinoma through NETosis-mediated skeletal muscle atrophy
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摘要 Abstract
中文摘要
目的：癌症恶病质以持续性体重减轻、骨骼肌萎缩和脂肪组织减少为特征——其中进行性骨骼肌消耗是主要表现——是胰腺导管腺癌（PDAC）患者死亡的主要原因之一。恶病质是 PDAC 常见且严重的并发症，显著影响患者的生活质量和预后。本研究探讨线粒体钙单向转运体（MCU）在 PDAC 相关恶病质中的作用，可能为其预防提供新的干预策略。
实验设计：分析了 PDAC 患者组织中 MCU 的表达，并将其与恶病质发生率相关联。建立了使用 MCU 过表达和对照稳定细胞系的自发肿瘤模型和原位 PDAC 模型，以评估肿瘤进展和肌肉萎缩。通过 H3cit/MPO/DAPI 多重免疫荧光检测中性粒细胞胞外诱捕网（NETs）的形成。通过抗 Ly6G 介导的中性粒细胞清除、DNase I 处理和 Pad4⁻/⁻ 小鼠检验 NETs 功能。分泌组分析确定了 MCU 调控 NETs 形成的机制，并通过重组蛋白处理和受体抑制进行验证。使用基因敲除模型和 AAV9 介导的骨骼肌特异性沉默研究了 CCDC25 的作用。
结果：MCU 过表达与 PDAC 患者的恶病质发生率和骨骼肌质量减少显著相关。与 MCU 过表达组相比，对照小鼠表现出减弱的肿瘤生长和保留的肌肉质量，且独立于肿瘤负荷。MCU 过表达的 PDAC 模型在骨骼肌中显示出显著升高的 NETs 浸润，而 NETs 清除则防止了肌肉萎缩。MCU 过表达诱导了细胞衰老和衰老相关分泌表型（SASP）分泌（尤其是 C3 和 CXCL1），通过 C3aR 和 CXCR2 信号促进 NETosis。CCDC25 被确定为骨骼肌中关键的 NET DNA 受体，通过 RAC1 依赖的 ROS 产生介导肌肉萎缩。
结论：我们的研究揭示了一条新的信号通路，其中肿瘤 MCU 过表达促进细胞衰老和 SASP 分泌，通过 C3/CXCL1 信号驱动 NETs 形成。NETs 结合肌细胞上的 CCDC25 受体，激活 RAC1-ROS 信号通路，最终导致肌肉萎缩。
意义：这些发现确立了 MCU-NETs-CCDC25 轴作为 PDAC 相关恶病质的关键机制，并提示了多种治疗策略——包括 MCU 抑制、NETs 降解和 CCDC25 阻断——为缓解恶病质和保留癌症患者肌肉质量提供了新的方向。
查看英文原文 English abstract
Purpose: Cancer cachexia, characterized by persistent weight loss, skeletal muscle atrophy, and adipose tissue reduction-with progressive skeletal muscle wasting being the predominant manifestation-represents a major cause of mortality in pancreatic ductal adenocarcinoma (PDAC) patients. Cachexia is a common and severe complication in PDAC, significantly impacting patients' quality of life and prognosis. This study investigates the role of the mitochondrial calcium uniporter (MCU) in PDAC-associated cachexia, potentially offering novel interventional strategies for its prevention.
Experimental Design: MCU expression was analyzed in PDAC patient tissues and correlated with cachexia incidence. Spontaneous tumor models and orthotopic PDAC models using MCU-overexpressing and control stable cell lines were established to evaluate tumor progression and muscle atrophy. Neutrophil extracellular traps (NETs) formation was detected by H3cit/MPO/DAPI multiplex immunofluorescence. NETs function was examined through anti-Ly6G-mediated neutrophil depletion, DNase I treatment, and Pad4⁻/⁻ mice. Secretome analysis identified MCU-regulated mechanisms in NETs formation, validated through recombinant protein treatment and receptor inhibition. The role of CCDC25 was investigated using genetic knockout models and AAV9-mediated skeletal muscle-specific silencing.
Results: MCU overexpression significantly correlated with cachexia incidence and reduced skeletal muscle mass in PDAC patients. Compared to the MCU-overexpression group, control mice demonstrated attenuated tumor growth and preserved muscle mass independent of tumor burden. MCU-overexpressing PDAC models showed significantly elevated NETs infiltration in skeletal muscle, while NETs clearance prevented muscle atrophy. MCU overexpression induced cellular senescence and senescence-associated secretory phenotype (SASP) secretion (particularly C3 and CXCL1), promoting NETosis through C3aR and CXCR2 signaling. CCDC25 was identified as a critical NET DNA receptor in skeletal muscle, mediating muscle atrophy through RAC1-dependent ROS production.
Conclusion: Our study reveals a novel signaling pathway wherein tumor MCU overexpression promotes cellular senescence and SASP secretion, driving NETs formation through C3/CXCL1 signaling. NETs engage CCDC25 receptors on muscle cells, activating the RAC1-ROS signaling pathway that ultimately leads to muscle atrophy.
Impact: These findings establish the MCU-NETs-CCDC25 axis as a key mechanism in PDAC-associated cachexia and suggest multiple therapeutic strategies-including MCU inhibition, NETs degradation, and CCDC25 blockade-providing new directions for alleviating cachexia and preserving muscle mass in cancer patients.
利益披露 Disclosure
X. Wang, None..
J. Hao, None.