Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer

  • Nat Commun. 2026 May 12;17(1):6328. doi: 10.1038/s41467-026-72932-5.
Guojun Chen  #  1 ,  Weicheng Lu  #  1 ,  Meng Liu  #  2 ,  Qingqing Ye  #  1 ,  Yixin Xu  1 ,  Yanqun Zhang  1 ,  Xiangna Guo  1 ,  Yaqi Ye  1 ,  Xiaohua Yang  1  3 ,  Xiaolin Luo  1 ,  Wenjun Xin  3  4 ,  Jingdun Xie  5
Affiliations
  • 1. Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2. Department of Anesthesia and Pain Medicine, Guangzhou First People's Hospital, Guangzhou, China.
  • 3. Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-sen University, Zhongshan Road 2, Guangzhou, China.
  • 4. Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.
  • 5. Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 42120379 DOI: 10.1038/s41467-026-72932-5
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.

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