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However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine\n                  <jats:italic>\n                    Kras\n                    <jats:sup>G12D<\/jats:sup>\n                  <\/jats:italic>\n                  -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified\n                  <jats:italic>Ntn1<\/jats:italic>\n                  upregulation, and then verified its\n                  <jats:italic>in vivo<\/jats:italic>\n                  upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the\n                  <jats:italic>Kras<\/jats:italic>\n                  mutation and \u03b2-adrenergic signaling, in part, through the MAPK pathway.\n                  <jats:italic>Ex-vivo<\/jats:italic>\n                  culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the\n                  <jats:italic>\n                    Pdx1-Cre;LSL-Kras\n                    <jats:sup>G12D\/+<\/jats:sup>\n                  <\/jats:italic>\n                  model,\n                  <jats:italic>Ntn1<\/jats:italic>\n                  knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In\n                  <jats:italic>\n                    Pdx1-Cre;LSL-Kras\n                    <jats:sup>G12D\/+<\/jats:sup>\n                    ;LSL-Trp53\n                    <jats:sup>R172H\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mice,\n                  <jats:italic>Ntn1<\/jats:italic>\n                  knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of\n                  <jats:italic>Neo1<\/jats:italic>\n                  reduced ZEB1 and SOX9 and decreased tumor progression. In contrast,\n                  <jats:italic>Ntn1<\/jats:italic>\n                  overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1\/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1\/NEO1 axis could represent a potential therapeutic approach for PDAC.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>NTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"666009v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.22.666009","type":"posted-content","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T22:50:15Z","timestamp":1753570215000},"source":"Crossref","is-referenced-by-count":0,"title":["Netrin-1 promotes pancreatic tumorigenesis and innervation through 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