2. Academic Validation
  3. Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1

  • bioRxiv. 2025 Jul 26:2025.07.22.666009. doi: 10.1101/2025.07.22.666009.
Yosuke Ochiai 1 2,  Hiroki Kobayashi 1,  Masaki Sunagawa 1 2,  Taisuke Baba 2,  Ermanno Malagola 1,  Feijing Wu 1,  Takayuki Tanaka 1 3,  Masahiro Hata 1,  Junya Arai 1,  Zhengyu Jiang 1,  Ruth A White 4,  Xiaofei Zhi 1,  Jin Qian 1,  Quin T Waterbury 1,  Ruhong Tu 1,  Biyun Zheng 1,  Yi Zeng 1,  Hualong Zheng 1,  Puran Zhang 1,  Shuang Li 1,  Leah B Zamechek 1,  Jonathan S LaBella 1,  Takahiro Sugie 5 6,  Tadashi Iida 5 7,  Atsushi Enomoto 5 6,  Holger K Eltzschig 8,  Carmine F Palermo 1,  Iok In Christine Chio 9,  Kenneth P Olive 1,  Timothy C Wang 1
Affiliations

Affiliations

  • 1 Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
  • 2 Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan.
  • 3 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
  • 4 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA.
  • 5 Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan.
  • 6 Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan.
  • 7 Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan.
  • 8 Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 9 Department of Genetics & Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
PMID: 40777309 DOI: 10.1101/2025.07.22.666009
Abstract

Nerves have been shown to regulate Cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine KrasG12D -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and β-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-KrasG12D/+ model, Ntn1 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 Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ mice, Ntn1 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 Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 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.

Keywords

Neogenin-1; Netrin-1; epithelial-mesenchymal transition; pancreatic cancer; sympathetic nerve.

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