Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor beta Signaling

Weissmueller, S., Manchado, E., Saborowski, M., Morris, J. P. th, Wagenblast, E., Davis, C. A., Moon, S. H., Pfister, N. T., Tschaharganeh, D. F., Kitzing, T., Aust, D., Markert, E. K., Wu, J., Grimmond, S. M., Pilarsky, C., Prives, C., Biankin, A. V., Lowe, S. W. (April 2014) Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor beta Signaling. Cell, 157 (2). pp. 382-94. ISSN 1097-4172 (Electronic)0092-8674 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24725405
DOI: 10.1016/j.cell.2014.01.066

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > metastasis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Gingeras lab
CSHL labs > Hannon lab
CSHL labs > Lowe lab
Watson School > Publications
Depositing User: Matt Covey
Date: 10 April 2014
Date Deposited: 18 Apr 2014 16:48
Last Modified: 29 Sep 2014 18:21
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29772

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