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

Susann Weissmueller, Eusebio Manchado, Michael Saborowski, John P. Morris IV, Elvin Wagenblast, Carrie A. Davis, Sung Hwan Moon, Neil T. Pfister, Darjus F. Tschaharganeh, Thomas Kitzing, Daniela Aust, Elke K. Markert, Jianmin Wu, Sean M. Grimmond, Christian Pilarsky, Carol Prives, Andrew V. Biankin, Scott W. Lowe

Research output: Contribution to journalArticlepeer-review

389 Scopus citations

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.

Original languageEnglish
Pages (from-to)382-394
Number of pages13
JournalCell
Volume157
Issue number2
DOIs
StatePublished - 10 Apr 2014
Externally publishedYes

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