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Cell. 2014 Apr 10;157(2):382-394. doi: 10.1016/j.cell.2014.01.066.

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

Author information

1
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
4
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
5
Department of Visceral, Thoracic and Vascular Surgery, Technical University of Dresden, 01062 Dresden, Germany.
6
The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA.
7
The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
8
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Santa Lucia 4072, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 1BD, UK.
9
The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney NSW 2010, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 1BD, UK.
10
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.

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.

PMID:
24725405
PMCID:
PMC4001090
DOI:
10.1016/j.cell.2014.01.066
[Indexed for MEDLINE]
Free PMC Article

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