肿瘤衍生的GDF15诱导CCN3⁺ 施旺细胞促进癌症疼痛的胰腺癌症
Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.
摘要(中文译文)
肿瘤-神经交互作用参与肿瘤微环境的重塑，然而肿瘤如何利用外周胶质网络，特别是施万细胞（SCs），来驱动慢性疼痛仍不清楚。在此，我们鉴定出一个特化的细胞通讯网络因子3阳性（CCN3⁺）施万细胞亚群，该亚群促进肿瘤神经支配并参与胰腺导管腺癌（PDAC）的疼痛。我们证明，癌细胞来源的生长分化因子15（GDF15）驱动CCN3⁺施万细胞扩增，并通过GDNF家族受体α样（GFRAL）受体诱导糖酵解重编程。机制上，GFRAL激活触发蛋白激酶B（AKT）-Runt相关转录因子2（RUNX2）级联反应，上调CCN3⁺施万细胞中的糖酵解酶肌肉型磷酸果糖激酶（PFKM），从而增强肿瘤神经支配和疼痛敏化。靶向抑制CCN3⁺施万细胞中的GDF15-GFRAL信号可显著缓解PDAC相关疼痛。总之，这些发现揭示了由施万细胞糖酵解重编程驱动的神经周围-代谢轴，并凸显了一种有前景的PDAC相关疼痛治疗策略。
Abstract
Tumor-neural crosstalk contributes to the remodeling of the tumor microenvironment, yet how tumors engage peripheral glial networks, particularly Schwann cells (SCs), to drive chronic pain remains unclear. Here, we identify a specialized cellular communication network factor 3-positive (CCN3⁺) SC subpopulation that promotes tumor innervation and contributes to pain in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that cancer cell-derived growth differentiation factor 15 (GDF15) drives expansion of CCN3⁺ SCs and induces glycolytic reprogramming via the GDNF family receptor alpha-like (GFRAL) receptor. Mechanistically, GFRAL activation triggers the protein kinase B (AKT)-runt-related transcription factor 2 (RUNX2) cascade, upregulating the glycolytic enzyme muscle-type phosphofructokinase (PFKM) in CCN3⁺ SCs, which enhances tumor innervation and pain sensitization. Targeted inhibition of GDF15-GFRAL signaling in CCN3⁺ SCs significantly alleviates PDAC-associated pain. Together, these findings reveal a perineural-metabolic axis driven by glycolytic reprogramming in SCs and highlight a promising therapeutic strategy for PDAC-associated pain.
如何引用
AMA
Guojun Chen, Weicheng Lu, Meng Liu, Qingqing Ye, Yixin Xu, Yanqun Zhang, et al. Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.. Nature communications. 2026; doi:10.1038/s41467-026-72932-5.
APA
Guojun Chen, Weicheng Lu, Meng Liu, Qingqing Ye, Yixin Xu, Yanqun Zhang, et al (2026). Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.. Nature communications. https://doi.org/10.1038/s41467-026-72932-5
GB/T 7714
Guojun Chen, Weicheng Lu, Meng Liu, Qingqing Ye, Yixin Xu, Yanqun Zhang, et al. Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72932-5.
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