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Cell Mol Gastroenterol Hepatol. 2019 Jul 13. pii: S2352-345X(19)30088-8. doi: 10.1016/j.jcmgh.2019.07.001. [Epub ahead of print]

Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis.

Author information

1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
2
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
3
Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
4
Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee.
5
Departments of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.
6
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Veterans Affairs, Tennessee Valley Health System, Nashville, Tennessee.
7
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
8
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: anna.means@vumc.org.

Abstract

BACKGROUND & AIMS:

Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known.

METHODS:

We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells.

RESULTS:

Although KrasG12D expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time.

CONCLUSIONS:

One mechanism by which tissues may be susceptible or resistant to KRASG12D-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.

KEYWORDS:

Acinar-to-Ductal Metaplasia; Cdkn1a; Cell of Origin; Pancreatic Duct Ligation

PMID:
31310834
DOI:
10.1016/j.jcmgh.2019.07.001
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