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Fibroblasts from distinct pancreatic pathologies exhibit disease-specific properties

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chron...

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Main Authors: Barrera, Lawrence N. (Author) , Evans, Anthony (Author) , Lane, Brian (Author) , Brumskill, Sarah (Author) , Oldfield, Frances E. (Author) , Campbell, Fiona (Author) , Andrews, Timothy (Author) , Lu, Zipeng (Author) , Perez-Mancera, Pedro A. (Author) , Liloglou, Triantafillos (Author) , Ashworth, Milton (Author) , Jalali, Mehdi (Author) , Dawson, Rebecca (Author) , Nunes, Quentin (Author) , Phillips, Phoebe A. (Author) , Timms, John F. (Author) , Halloran, Christopher (Author) , Greenhalf, William (Author) , Neoptolemos, John P. (Author) , Costello, Eithne (Author)
Format: Article (Journal)
Language:English
Published: May 11, 2020
In: Cancer research
Year: 2020, Volume: 80, Issue: 13, Pages: 2861-2873
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-19-3534
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-19-3534
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Author Notes:Lawrence N. Barrera, Anthony Evans, Brian Lane, Sarah Brumskill, Frances E. Oldfield, Fiona Campbell, Timothy Andrews, Zipeng Lu, Pedro A. Perez-Mancera, Triantafillos Liloglou, Milton Ashworth, Mehdi Jalali, Rebecca Dawson, Quentin Nunes, Phoebe A. Phillips, John F. Timms, Christopher Halloran, William Greenhalf, John P. Neoptolemos, and Eithne Costello
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Summary:Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGF beta 1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. Significance: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.
Item Description:Gesehen am 22.09.2020
Physical Description:Online Resource
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-19-3534

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