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Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties
Lawrence N Barrera1, Anthony Evans1, Brian Lane2
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
Cancer Research
|May 13, 2020
Summary
Pancreatic cancer and pancreatitis fibroblasts differ molecularly and functionally. These distinct disease-specific fibroblast characteristics impact pancreatic ductal adenocarcinoma progression and offer new research and therapeutic targets.
Area of Science:
- Gastroenterology and Hepatology
- Oncology
- Cell Biology
Background:
- Fibrotic stroma is crucial in pancreatic diseases.
- Phenotypic differences in fibroblasts across pancreatic diseases are not well understood.
Purpose of the Study:
- To investigate if fibroblasts from different pancreatic diseases exhibit distinct molecular and functional profiles.
- To identify specific markers and regulators differentiating these fibroblasts.
Main Methods:
- Isolation and culture of fibroblasts from pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and normal adjacent (NA) tissues.
- Analysis of mRNA and miRNA profiles.
- Assessment of fibroblast response to antifibrotic (NPPB) and activation (TGFβ1, WNT) stimuli.
- Quantification of tenascin C (TNC) and miR-137 levels.
- Evaluation of conditioned media effects on PDAC cell behavior.
- Measurement of circulating TNC levels.
Main Results:
- Fibroblasts from PDAC, CP, periampullary tumors, and NA tissues show distinct mRNA and miRNA profiles.
- PDAC fibroblasts are less sensitive to antifibrotic stimuli and more responsive to activation signals compared to NA fibroblasts.
- PDAC and CP fibroblasts share similarities, but PDAC fibroblasts have higher tenascin C (TNC) levels, regulated by miR-137.
- Higher TNC levels in PDAC tissue correlate with increased stromal activation.
- TNC depletion from PDAC fibroblasts partially enhances PDAC cell proliferation and migration, suggesting an inhibitory role for stromal TNC.
- Circulating TNC levels are elevated in PDAC patients compared to CP patients.
Conclusions:
- Pancreatic fibroblasts are programmed in a disease-specific manner, retaining distinct molecular and functional characteristics in culture.
- These findings provide valuable cellular models for disease-specific research and the development of targeted therapies for pancreatic diseases.
- Stromal TNC may play a complex, potentially inhibitory, role in PDAC progression.
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