Role of a transmembrane protein, epithelial membrane protein 1, in the pathogenesis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has two subtypes: the "classical/progenitor" type and "basal-like/squamous" type, the latter of which has poor clinical outcomes with no effective treatment strategies. We aimed to elucidate the role of epithelial membrane protein 1 (EMP1) in PDAC and its potential as a therapeutic target, particularly in aggressive disease such as "basal-like/squamous" type of PDAC. We examined the association of EMP1 expression using patient-derived organoids (PDOs) of human PDAC, K-RASLSL-G12D, Trp 53LSL-R172H, and Pdx1-Cre recombinase mice, human PDAC cell lines, and publicly available clinical datasets. The functional roles of EMP1 were evaluated in vitro and in vivo through its knockout and stable overexpression. EMP1 knockout reduced proliferation, metastasis, and drug resistance, whereas overexpression enhanced malignant features. Transcriptomic analysis revealed that EMP1 promotes epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the K-RAS signaling pathway. EMP1 expression is inversely implicated in the oxidative phosphorylation pathway, which is characteristic of the "classical/progenitor" type. Furthermore, integrated analysis revealed an association between EMP1 expression and ERK phosphorylation. EMP1 plays a crucial role in the pathogenesis of PDAC, as it contributes to the proliferative and metastatic characteristics of PDAC. This study suggests that EMP1 may be a potential therapeutic target gene for aggressive disease.