Abstract 105: Netrin-1 activates Yap1 to promote pancreatic cancer metastasis and mutant Kras-independence

Abstract Although pancreatic ductal adenocarcinoma (PDAC) is only the 10th most common cancer, it is the 3rd leading cause of cancer deaths due to its high incidence of metastasis. In patient samples, PDAC metastasis associates with expression of the secreted protein Netrin-1, and indeed metastasis of pancreatic adenocarcinomas in mouse models is sharply reduced upon genetic or pharmacological ablation of Ntn1 signaling. Upon binding to its Unc5b receptor, Ntn1 activates the survival factor Yap1, which then promotes resistance to anoikis, which is a key trait of metastatic tumors. But metastatic PDACs are not the only expressers of Ntn1: indeed, primary pancreatic tumors can also derepress Ntn1 if selected to grow in the absence of mutant Kras. These Krasmut-independent tumors become dependent upon activation of Yap1 by Ntn1/Unc5b signaling, and suggest that patients with pancreatic cancer may benefit from combined pharmacological targeting of mutant Kras and Ntn1. Citation Format: Chris R. Harris, Muhammad Sadeqi Nezhad, Shubhrika Jain, Wade Narrow, Darren R. Carpizo. Netrin-1 activates Yap1 to promote pancreatic cancer metastasis and mutant Kras-independence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 105.