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

Weissmueller, S. et al. (2014) Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell, 157(2), pp. 382-394. (doi:10.1016/j.cell.2014.01.066)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Grimmond, Professor Sean and Biankin, Professor Andrew
Authors: Weissmueller, S., Manchado, E., Saborowski, M., Morris, J. P., 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., and Lowe, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell
Publisher:Cell Press
ISSN:0092-8674
ISSN (Online):1097-4172
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