Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling

Weissmueller, Susann, Manchado, Eusebio, Saborowski, Michael, Morris IV, John P., Wagenblast, Elvin, Davis, Carrie A., Moon, Sung-Hwan, Pfister, Neil T., Tschaharganeh, Darjus F., Kitzing, Thomas, Aust, Daniela, Markert, Elke K., Wu, Jianmin, Grimmond, Sean M., Pilarsky, Christian, Prives, Carol, Biankin, Andrew V. and Lowe, Scott W. (2014) Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell, 157 2: 382-394. doi:10.1016/j.cell.2014.01.066


Author Weissmueller, Susann
Manchado, Eusebio
Saborowski, Michael
Morris IV, John P.
Wagenblast, Elvin
Davis, Carrie A.
Moon, Sung-Hwan
Pfister, Neil T.
Tschaharganeh, Darjus F.
Kitzing, Thomas
Aust, Daniela
Markert, Elke K.
Wu, Jianmin
Grimmond, Sean M.
Pilarsky, Christian
Prives, Carol
Biankin, Andrew V.
Lowe, Scott W.
Title Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
1097-4172
Publication date 2014-04-10
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.cell.2014.01.066
Open Access Status Not Open Access
Volume 157
Issue 2
Start page 382
End page 394
Total pages 13
Place of publication Cambridge, MA United States
Publisher Cell Press
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
Abstract Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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