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. 2025 Jul 17:S1535-6108(25)00270-3.
doi: 10.1016/j.ccell.2025.06.020. Online ahead of print.

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

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

Min-Min Chen et al. Cancer Cell. .
Free article

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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Conflict of interest statement

Declaration of interests Z.Z. is a founder of Analytical Bioscience and serves on the Advisory Board of Cell. All financial interests are unrelated to this study.

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