Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1

Area of Science:

• Oncology
• Neuroscience
• Molecular Biology

Background:

• Nerve regulation of cancer progression is known, but the role of axon guidance molecules in pancreatic cancer is unclear.
• Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with complex progression mechanisms.
• Understanding molecular drivers of PDAC tumorigenesis, innervation, and metastasis is crucial for therapeutic development.

Purpose of the Study:

• To investigate the role of axon guidance molecules, specifically Netrin-1 (NTN1), in pancreatic cancer.
• To elucidate the mechanisms by which NTN1 influences pancreatic tumorigenesis, innervation, and metastasis.
• To evaluate the therapeutic potential of targeting the NTN1/NEO1 axis in PDAC.

Main Methods:

• Screening of axon guidance molecules using qRT-PCR in murine Kras-mutant pancreatic organoids.
• In vivo validation of NTN1 upregulation in human and mouse pancreatic tumors.
• Ex vivo studies of sympathetic neuron axonogenesis and organoid/mouse models of PDAC progression and metastasis.
• Genetic manipulation (knockout/overexpression) and antibody-based inhibition of the NTN1/NEO1 axis.

Main Results:

• NTN1 and its receptor NEO1 are upregulated in PDAC, driven by Kras mutation and beta-adrenergic signaling via MAPK.
• NTN1 promotes sympathetic nerve axonogenesis and PDAC progression, enhancing cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness.
• Inhibition of NTN1/NEO1 axis reduced innervation, EMT, stemness markers (ZEB1, SOX9), and liver metastasis, extending survival in mouse models.

Conclusions:

• The NTN1/NEO1 axis is a critical regulator of PDAC progression, impacting both cancer cells and tumor innervation.
• NTN1 directly promotes cancer stemness and EMT, and indirectly fuels tumor growth via nerve stimulation.
• Targeting the NTN1/NEO1 axis represents a promising therapeutic strategy for pancreatic ductal adenocarcinoma.