| First Author | Kobayashi H | Year | 2026 |
| Journal | Cancer Res | Volume | 86 |
| Issue | 8 | Pages | 1883-1901 |
| PubMed ID | 41474982 | Mgi Jnum | J:385511 |
| Mgi Id | MGI:8332451 | Doi | 10.1158/0008-5472.CAN-25-2243 |
| Citation | Kobayashi H, et al. (2026) Netrin-1 Promotes Pancreatic Tumorigenesis and Innervation through NEO1. Cancer Res 86(8):1883-1901 |
| abstractText | Nerves can regulate tumorigenesis and cancer progression. However, clarification of the role of axon guidance molecules in tumorigenesis, innervation, and metastasis is required to better understand the tumor-promoting functions of nerves. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules and identified netrin-1 upregulation. Netrin-1 was also upregulated in vivo during pancreatic tumorigenesis in humans and mice. Mutant KRAS and beta-adrenergic signaling upregulated netrin-1 and its receptor NEO1 in epithelial cells in part through the MAPK pathway. Ex vivo culture of celiac ganglia showed that netrin-1 promoted the axonogenesis of sympathetic neurons through nerve NEO1. In the Pdx1-Cre;LSL-KrasG12D/+ model, knockout (KO) of Ntn1, which encodes netrin-1, decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant netrin-1 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 Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ mice, Ntn1 KO reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of pancreatic ductal adenocarcinoma (PDAC), treatment with a netrin-1-neutralizing antibody or tumoral KO of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, netrin-1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the netrin-1/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 netrin-1 pathway could represent a potential therapeutic approach for PDAC. SIGNIFICANCE: Netrin-1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve cross-talk in cancer and the potential of netrin-1 blockade as a treatment strategy. |
