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

Publication ,  Journal Article
Shi, C; Pan, FC; Kim, JN; Washington, MK; Padmanabhan, C; Meyer, CT; Kopp, JL; Sander, M; Gannon, M; Beauchamp, RD; Wright, CV; Means, AL
Published in: Cell Mol Gastroenterol Hepatol
2019

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.

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Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2019

Volume

8

Issue

4

Start / End Page

579 / 594

Location

United States

Related Subject Headings

  • Signal Transduction
  • Proto-Oncogene Proteins p21(ras)
  • Precancerous Conditions
  • Pancreatitis, Chronic
  • Pancreatic Neoplasms
  • Mutation
  • Mice
  • Metaplasia
  • Genes, ras
  • Disease Models, Animal
 

Citation

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Shi, C., Pan, F. C., Kim, J. N., Washington, M. K., Padmanabhan, C., Meyer, C. T., … Means, A. L. (2019). Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis. Cell Mol Gastroenterol Hepatol, 8(4), 579–594. https://doi.org/10.1016/j.jcmgh.2019.07.001
Shi, Chanjuan, Fong Cheng Pan, Jessica N. Kim, M Kay Washington, Chandrasekhar Padmanabhan, Christian T. Meyer, Janel L. Kopp, et al. “Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis.Cell Mol Gastroenterol Hepatol 8, no. 4 (2019): 579–94. https://doi.org/10.1016/j.jcmgh.2019.07.001.
Shi C, Pan FC, Kim JN, Washington MK, Padmanabhan C, Meyer CT, et al. Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis. Cell Mol Gastroenterol Hepatol. 2019;8(4):579–94.
Shi, Chanjuan, et al. “Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis.Cell Mol Gastroenterol Hepatol, vol. 8, no. 4, 2019, pp. 579–94. Pubmed, doi:10.1016/j.jcmgh.2019.07.001.
Shi C, Pan FC, Kim JN, Washington MK, Padmanabhan C, Meyer CT, Kopp JL, Sander M, Gannon M, Beauchamp RD, Wright CV, Means AL. Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis. Cell Mol Gastroenterol Hepatol. 2019;8(4):579–594.
Journal cover image

Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2019

Volume

8

Issue

4

Start / End Page

579 / 594

Location

United States

Related Subject Headings

  • Signal Transduction
  • Proto-Oncogene Proteins p21(ras)
  • Precancerous Conditions
  • Pancreatitis, Chronic
  • Pancreatic Neoplasms
  • Mutation
  • Mice
  • Metaplasia
  • Genes, ras
  • Disease Models, Animal