Ruth A. White

Supplemental Table 1. Specific Medications

Background:Neural regulation contributes to pancreatic ductal adenocarcinoma (PDAC) development, but effects of neural-targeting medications on presentation or outcomes remain unclear. Methods:We conducted a retrospective study using the Veterans Affairs (VA) Corporate Data Warehouse (CDW) to identify patients with pancreatic cancer (2000–2020). Exposure to β-blockers, cholinergics, or statins was defined by active prescriptions within 6 months before or 1 month after diagnosis. Outcomes included histologic subtype, stage, and overall survival (OS). Propensity score matching was performed for each medication class, with survival assessed using Kaplan–Meier and Cox regression models. Results:Among 7,578 veterans with pancreatic cancer, 76% had adenocarcinoma and 60% presented with stage IV disease. β-Blocker use was associated with lower odds of advanced stage [odds ratio (OR), 0.55; 95% confidence interval (CI), 0.5–0.63; P < 0.0001] and improved OS [hazard ratio (HR), 0.89; 95% CI, 0.84–0.95; P < 0.0001]. Cholinergic agonist use was associated with reduced likelihood of adenocarcinoma histology (OR, 0.64; 95% CI, 0.41–1.01; P = 0.051) and advanced stage (OR, 0.53; 95% CI, 0.34–0.85; P = <0.0001) but not OS. Statin use was associated with adenocarcinoma histology (OR, 1.24; 95% CI, 1.09–1.43; P = 0.002) and lower odds of advanced stage (OR, 0.77; 95% CI, 0.68–0.88; P = <0.0001). Conclusions:β-Blockers were associated with earlier stage and improved survival. Cholinergic agonists and statins were associated with earlier stage. Cholinergic agonists were linked to lower likelihood of adenocarcinoma histology, whereas statins were linked to higher likelihood. These findings suggest that neural and metabolic pathways may shape early PDAC biology. Impact:Autonomic and metabolic pathways may influence PDAC biology. β-Blockers merit mechanistic and clinical evaluation as adjunctive therapies.

Supplemental Table 2. Sensitivity Analysis

Background: Neural regulation contributes to pancreatic ductal adenocarcinoma (PDAC) development, but effects of neural-targeting medications on presentation or outcomes remain unclear. Methods: We conducted a retrospective study using the Veterans Affairs (VA) Corporate Data Warehouse (CDW) to identify patients with pancreatic cancer (2000–2020). Exposure to β-blockers, cholinergics, or statins was defined by active prescriptions within 6 months before or 1 month after diagnosis. Outcomes included histologic subtype, stage, and overall survival (OS). Propensity score matching was performed for each medication class, with survival assessed using Kaplan–Meier and Cox regression models. Results: Among 7,578 veterans with pancreatic cancer, 76% had adenocarcinoma and 60% presented with stage IV disease. β-Blocker use was associated with lower odds of advanced stage [odds ratio (OR), 0.55; 95% confidence interval (CI), 0.5–0.63; P < 0.0001] and improved OS [hazard ratio (HR), 0.89; 95% CI, 0.84–0.95; P < 0.0001]. Cholinergic agonist use was associated with reduced likelihood of adenocarcinoma histology (OR, 0.64; 95% CI, 0.41–1.01; P = 0.051) and advanced stage (OR, 0.53; 95% CI, 0.34–0.85; P = <0.0001) but not OS. Statin use was associated with adenocarcinoma histology (OR, 1.24; 95% CI, 1.09–1.43; P = 0.002) and lower odds of advanced stage (OR, 0.77; 95% CI, 0.68–0.88; P = <0.0001). Conclusions: β-Blockers were associated with earlier stage and improved survival. Cholinergic agonists and statins were associated with earlier stage. Cholinergic agonists were linked to lower likelihood of adenocarcinoma histology, whereas statins were linked to higher likelihood. These findings suggest that neural and metabolic pathways may shape early PDAC biology. Impact: Autonomic and metabolic pathways may influence PDAC biology. β-Blockers merit mechanistic and clinical evaluation as adjunctive therapies.

Figure S10 shows that treatment with the NTN1-neutralizing antibody reduces tumor growth, FAK phosphorylation, and innervation in an mT4 liver metastasis model, improves mouse survival, and decreases tumor burden in a Panc02 liver metastasis model.

Figure S6 shows that Ntn1 knockout decreases innervation, reduces CD11b+ myeloid cells, and increases CD8+ T cells in KPC tumors.

Figure S9 shows that tumoral Neo1 knockout reduces the growth of PDAC liver metastasis in mT4 and Panc02 splenic injection models.

Figure S5 shows that β-adrenergic stimulation increases mT4 PDAC cell growth and migration while upregulating stemness- and EMT-related genes.

Figure S1 shows that Ntn1 and Neo1 are upregulated in mouse pancreatic tumor cells and that high expression of NTN1 and NEO1 is associated with shorter overall survival in patients with PDAC.

Figure S2 shows that KrasG12D mutation and β-adrenergic stimulation upregulate Ntn1 and Neo1 through MAPK pathway-mediated interaction of ELK1 (for Ntn1) or c-JUN (for Neo1) with their promoter regions.