Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.

ABSTRACT: Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRAS^G12D and TP53^R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRAS^MUT-dependent ARF6 signa

SUBMITTER: Thielman NRJ 

PROVIDER: S-EPMC11801256 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature