Abstract A068: Lfng-expressing centroacinar cell is a prime cell-of-origin for p53-deficient pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with poor understanding of etiology. Studies using mouse models showed that both acinar and ductal cells of the pancreas can be transformed by combination of oncogenic Kras and p53 mutations to form PDAC. How the transforming capacities of pancreatic cells are constrained, or whether a unique subset of cells serve as a prime target for oncogenic transformation, remains obscure. We found that expression of a Notch modulator, Lunatic Fringe (Lfng), is confined to a limited number of cells with centroacinar location and morphology in the adult mouse pancreas. These cells are selectively targeted by KrasG12D coupled with p53 loss-of-function (but not gain-of-function) mutations, leading to rapid pancreatic tumor formation, whereas the elimination of Lfng completely blocks the initiation of these tumors. We showed that p53 constrains the progenitor-like property of Lfng-expressing cells and that Lfng is required for hyperproliferation of these cells when p53 is inactivated. We identified Notch3 as a functional Notch receptor for PDAC initiation and progression in this context. Lfng expression is undetectable in normal acinar and ductal cells but upregulated in acinar- as well as ductal-derived precursor lesions, and its deletion hinders both the initiation and progression of these lesions. Collectively, Lfng marks a centroacinar subpopulation that is restrained by p53 and is uniquely susceptible to oncogenic transformation with p53 loss. Furthermore, Lfng functions as an oncogene in all three exocrine lineages in the adult pancreas. Genetic alterations of LFNG, predominantly in the forms of mRNA upregulation and gene amplification, were detected in 9% of PDAC patients and were associated with shortened overall survival. Consistent with its expression in mouse pancreas, LFNG immunostaining was noted in a subset of centroacinar cells in normal adjacent pancreatic tissues from human patients, and its expression in the adenocarcinoma specimens was positively correlated to tumor grade. Thus, LFNG may play an important role in human PDAC, in parallel with the one shown in the murine models. This study offers new insights into the pancreatic cancer cell-of-origin, initiation, and progression, which may lead to the identification of a therapeutic target for the disease. Citation Format: Keli Xu, Wen-Cheng Chung, Shubing Zhang, Azeddine Atfi. Lfng-expressing centroacinar cell is a prime cell-of-origin for p53-deficient pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A068.