PO.TB10.13 · 肿瘤生物学
衰老的癌症相关成纤维细胞驱动胰腺导管腺癌的神经周围浸润和疼痛
Senescent cancer-associated fibroblasts drive perineural invasion and pain in pancreatic ductal adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）疼痛与神经周围浸润（PNI）相关，严重损害生活质量，并预示不良预后。驱动这一PNI-疼痛轴的机制，尤其是衰老的癌症相关成纤维细胞（senCAFs）的作用，以及有效的治疗方法仍不明确。
方法：我们在两个PDAC队列中将疼痛评分（NRS）与PNI（IHC/IF）相关联。进行了单细胞/空间转录组学和脂质组学分析，并与外部数据集交叉验证。将人/鼠senCAFs与肿瘤细胞、背根神经节（DRG）神经元及患者来源类器官（PDOs）共培养，通过膜片钳电生理评估神经元活性。体内研究采用成纤维细胞特异性敲除的原位模型，通过行为学和伤害感受分析进行评估。
结果：更高的疼痛分级与增加的PNI、神经密度及不良预后密切相关。scRNA-seq和空间分析揭示p16+ senCAFs在神经附近富集，并经流式细胞术在疼痛肿瘤中确认。senCAFs原位共接种在肿瘤负荷出现差异之前即诱导伤害感受性超敏。机制上，senCAFs激活IL-6-JAK2/STAT3反馈环，使DRG神经元敏化。JAK2阻断使神经元兴奋性正常化并减少疼痛行为。这种神经-基质串扰是双向的：senCAFs通过IL-6-JAK2/STAT3使DRG敏化，而激活的DRG释放ATP，触发P2RX7介导的肿瘤细胞去极化以促进浸润。此环路由肿瘤来源的、SPHK2依赖的S1P信号经CAF上的S1PR2稳定，强化衰老表型。体内，JAK2抑制联合nab-紫杉醇/吉西他滨显著改善疼痛控制和总生存。
结论：p16+ senCAFs通过激活IL-6-JAK2/STAT3通路编排一个恶性循环，增强神经元放电和疼痛；这反过来放大ATP/P2RX7驱动的肿瘤细胞去极化和进展。此循环由肿瘤来源的CAF鞘脂重编程稳定。通过JAK2抑制靶向这一senCAF驱动的神经-基质轴，联合标准化疗，为PDAC相关疼痛提供了一种转化上有效的治疗策略。
查看英文原文 English abstract
Background Pain in pancreatic ductal adenocarcinoma (PDAC) correlates with perineural invasion (PNI), severely impairs quality of life, and predicts poor prognosis. The mechanisms driving this PNI-pain axis, particularly the role of senescent cancer-associated fibroblasts (senCAFs), and effective therapies remain elusive.
Methods We correlated pain scores (NRS) with PNI (IHC/IF) in two PDAC cohorts. Single-cell/spatial transcriptomics and lipidomics were performed and cross-validated with external datasets. Human/murine senCAFs were co-cultured with tumor cells, dorsal root ganglion (DRG) neurons, and patient-derived organoids (PDOs), with neuronal activity assessed via patch-clamp electrophysiology. In vivo studies utilized orthotopic models with fibroblast-specific knockouts, evaluated by behavioral and nociceptive analyses.
Results Higher pain grades strongly correlated with increased PNI, nerve density, and poor prognosis. scRNA-seq and spatial analyses revealed p16+ senCAFs enriched near nerves, confirmed by flow cytometry in painful tumors. Orthotopic co-inoculation with senCAFs induced nociceptive hypersensitivity prior to differences in tumor burden. Mechanistically, senCAFs activated an IL-6-JAK2/STAT3 feedback loop, sensitizing DRG neurons. JAK2 blockade normalized neuronal excitability and reduced pain behaviors. This neural-stromal crosstalk was bidirectional: senCAFs sensitize DRGs via IL-6-JAK2/STAT3, while activated DRGs release ATP, triggering P2RX7-mediated tumor cell depolarization to promote invasion. This loop is stabilized by tumor-derived, SPHK2-dependent S1P signaling via S1PR2 on CAFs, reinforcing the senescent phenotype. In vivo, JAK2 inhibition combined with nab-paclitaxel/gemcitabine significantly improved pain control and overall survival.
Conclusion p16+ senCAFs orchestrate a vicious cycle by activating the IL-6-JAK2/STAT3 pathway, enhancing neuronal firing and pain; this in turn amplifies ATP/P2RX7-driven tumor cell depolarization and progression. This cycle is stabilized by tumor-derived sphingolipid reprogramming of CAFs. Targeting this senCAF-driven neural-stromal axis via JAK2 inhibition, combined with standard chemotherapy, provides a translationally potent therapeutic strategy for PDAC-related pain.
利益披露 Disclosure
J. Lu, None..
Z. Tu, None..
S. Zhu, None..
H. Lin, None..
Y. Chen, None..
Y. Chen, None..
Z. Wang, None..
H. Zhang, None..
S. Chen, None.