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Updated: Jun 7, 2025
Pancreatic Tissue Dissection to Isolate Viable Single Cells
Published on: May 26, 2023
Lfng-expressing centroacinar cell is a unique cell-of-origin for p53 deficient pancreatic cancer
Wen-Cheng Chung1,2, Shubing Zhang3, Azeddine Atfi4
1Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, 39216, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited understanding of etiology. Studies in mice showed that both acinar and ductal cells of the pancreas can be targeted by combination of oncogenic Kras and p53 mutations to form PDAC. How the transforming capacities of pancreatic cells are constrained, and whether a subset of cells could serve as a prime target for oncogenic transformation, remain obscure. Here we report that expression of a Notch modulator, Lunatic Fringe (Lfng), is restricted to a limited number of cells with centroacinar location and morphology in the adult pancreas. Lfng-expressing cells are preferentially targeted by oncogenic Kras along with p53 deletion to form PDAC, and deletion of Lfng blocks tumor initiation from these cells. Notch3 is a functional Notch receptor for PDAC initiation and progression in this context. Lfng is upregulated in acinar- and ductal-derived PDAC and its deletion suppresses these tumors. Finally, high LFNG expression is associated with high grade and poor survival in human patients. Taken together, Lfng marks a centroacinar subpopulation that is uniquely susceptible to oncogenic transformation when p53 is lost, and Lfng functions as an oncogene in all three lineages of the exocrine pancreas.
Insights
Lunatic Fringe (Lfng) marks specific pancreatic cells susceptible to cancer when p53 is lost. Lfng acts as an oncogene in pancreatic ductal adenocarcinoma (PDAC) development and progression.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with poorly understood origins.
- Previous studies indicated that oncogenic Kras and p53 mutations can induce PDAC from pancreatic acinar and ductal cells in mice.
- The specific cellular targets and constraints on transformation capacity remain unclear.
Purpose of the Study:
- To identify specific pancreatic cell populations susceptible to oncogenic transformation.
- To investigate the role of Lunatic Fringe (Lfng) in pancreatic cancer initiation and progression.
- To explore the therapeutic potential of targeting Lfng in PDAC.
Main Methods:
- Analysis of Lfng expression in adult mouse pancreas.
- Genetic manipulation of Lfng, Kras, and p53 in mouse models.
- Assessment of PDAC formation and tumor growth.
- Investigation of Notch3 receptor involvement.
- Analysis of human PDAC patient data for LFNG expression correlation.
Main Results:
- Lfng expression is restricted to a specific subpopulation of centroacinar cells in the adult pancreas.
- These Lfng-expressing cells are preferentially targeted by oncogenic Kras and p53 deletion to form PDAC.
- Lfng deletion inhibits tumor initiation, while its upregulation is observed in PDAC and promotes tumor growth.
- Notch3 acts as a functional receptor in PDAC initiation and progression.
- High LFNG expression in human PDAC correlates with high grade and poor patient survival.
Conclusions:
- Lfng identifies a unique centroacinar cell population susceptible to transformation upon p53 loss.
- Lfng functions as an oncogene in PDAC development across multiple cell lineages.
- Targeting Lfng presents a potential therapeutic strategy for pancreatic cancer.
