2. Academic Validation
  3. Integrated single-cell and spatial transcriptomics uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer

Integrated single-cell and spatial transcriptomics uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer

  • Cancer Cell. 2025 Sep 8;43(9):1656-1676.e10. doi: 10.1016/j.ccell.2025.06.020.
Min-Min Chen 1,  Qinhang Gao 2,  Huiheng Ning 3,  Kang Chen 3,  Yang Gao 3,  Min Yu 4,  Chao-Qun Liu 5,  Wei Zhou 3,  Jieying Pan 3,  Lusheng Wei 4,  Wenxian Dou 5,  Dingwen Zhang 4,  Linnan Zhu 6,  Qingling Zhang 7,  Rufu Chen 8,  Zemin Zhang 9
Affiliations

Affiliations

  • 1 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China. Electronic address: chenmm_szbl@outlook.com.
  • 2 Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China.
  • 3 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 4 Department of Pancreatic Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 5 Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 6 Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China.
  • 7 Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. Electronic address: zhangqingling@gdph.org.cn.
  • 8 Department of Pancreatic Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. Electronic address: chenrf63@163.com.
  • 9 Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China; Chongqing Medical University, Chongqing, China. Electronic address: zemin@pku.edu.cn.
PMID: 40680743 DOI: 10.1016/j.ccell.2025.06.020
Abstract

Nerves are integral to tumor biology, yet the peri- and intra-neural microenvironment and their roles in cancer-neural invasion (NI) remain underexplored. Here, we perform single-cell/single-nucleus RNA Sequencing (sc/snRNA-seq) and spatial transcriptomics on 62 samples from 25 pancreatic ductal adenocarcinoma (PDAC) patients, mapping cellular composition, lineage dynamics, and spatial organization across varying NI statuses. Tertiary lymphoid structures are abundant in low-NI tumor tissues and co-localize with non-invaded nerves, while NLRP3+ macrophages and cancer-associated myofibroblasts surround invaded nerves in high-NI tissues. We identify a unique endoneurial NRP2+ fibroblast population and characterize three distinct Schwann cell subsets. TGFBI+ Schwann cells locate at the leading edge of NI, can be induced by transforming growth factor β (TGF-β) signaling, promote tumor cell migration, and correlate with poor survival. We also identify basal-like and neural-reactive malignant subpopulations with distinct morphologies and heightened NI potential. This landscape depicting tumor-associated nerves highlights critical cancer-immune-neural interactions in situ and enlightens treatment development targeting NI.

Keywords

NI; PDAC; Schwann cells; TLSs; TME; endoneurial fibroblast; neural invasion; neuro-immuno-oncology; pancreatic ductal adenocarcinoma; single-cell RNA sequenceing; spatial transcriptomics; tertiary lymphoid structures; tumor microenvironment; tumor-associated nerves.

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