Fig. 1: Ablation of nociceptor neurons suppresses PDAC development and cancer pain.

a CGRP⁺ nociceptive nerves or β-tubulin III-labeled total nerves in normal pancreas or PDAC tissues from patients. Left, representative images of hematoxylin & eosin and immunofluorescence staining; right, quantification (n = 5 patients/group). Normal pancreas was obtained from the adjacent pancreatic tissues from patients with benign pancreatic lesion (serous cystic neoplasm of the pancreas). Scale bar, 100 μm. The same sections were also stained for TH and ChAT (Supplementary information, Fig. S3g). b Expression of CGRP in murine normal pancreas and PDAC tissue. Top, representative images; bottom, quantification (n = 5 mice/group). Scale bar, 50 μm. c Experimental scheme for chemical ablation of TRPV1⁺ nociceptor neurons and tumor measurement. C57BL/6 mice at 4 weeks of age were treated with RTX (30 μg/kg, 70 μg/kg, and 100 μg/kg) subcutaneously for 3 consecutive days. Mice were rested for 4 weeks before orthotopic inoculation with KPC cells (5 × 10⁴ cells/mouse) into pancreas. d Hot plate test to determine the heat sensitivity. Left, diagram of hot plate test; right, quantification of latency time (n = 8 mice/group). e In vivo bioluminescence of fluxes emitted by KPC cells in vehicle- or RTX-treated tumor-bearing mice at 1, 3, 5 and 7 weeks post inoculation. Left, images were obtained at 15 min after D-luciferin injection (30 mg/kg, intraperitoneally (i.p.)); right, quantification of luciferase activity (n = 8 mice/group). f Tumor weights were compared between the vehicle and RTX groups. Left, images of tumors harvested 7 weeks post inoculation; right, quantification of tumor weight (n = 8 mice/group). g Survival analysis of tumor-bearing mice treated with vehicle or RTX (n = 10 mice/group). h Von Frey test measured the upper abdominal mechanical pain associated with cancer in mice treated with vehicle or RTX at baseline (BL), 3, 5, and 7 weeks after KPC inoculation. i CPA test was conducted to assess hypersensitivity to mechanical stimulation elicited by 0.02 g von Frey filament. Top, brief protocol of CPA test; bottom, representative traces and quantification (n = 7 mice/group). j Open field test was performed at 7 weeks after tumor inoculation to determine the distance (mm) and mean speed (mm/s) over a 20 min duration in vehicle- or RTX-treated mice (n = 7 mice/group). Top, representative traces; bottom, quantification. Data are shown as mean ± SEM; ns not significant, *P < 0.05, **P < 0.01, ***P < 0.001.