Title |
Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling
|
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Published in |
Cell, April 2014
|
DOI | 10.1016/j.cell.2014.01.066 |
Pubmed ID | |
Authors |
Susann Weissmueller, Eusebio Manchado, Michael Saborowski, John P. Morris, 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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 29% |
United Kingdom | 1 | 14% |
Portugal | 1 | 14% |
Unknown | 3 | 43% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 5 | 71% |
Scientists | 1 | 14% |
Practitioners (doctors, other healthcare professionals) | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 6 | 1% |
Hungary | 1 | <1% |
Netherlands | 1 | <1% |
Austria | 1 | <1% |
Australia | 1 | <1% |
Germany | 1 | <1% |
Belgium | 1 | <1% |
United Kingdom | 1 | <1% |
Japan | 1 | <1% |
Other | 1 | <1% |
Unknown | 467 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 126 | 26% |
Researcher | 100 | 21% |
Student > Bachelor | 51 | 11% |
Student > Master | 47 | 10% |
Student > Doctoral Student | 27 | 6% |
Other | 62 | 13% |
Unknown | 69 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 140 | 29% |
Agricultural and Biological Sciences | 130 | 27% |
Medicine and Dentistry | 75 | 16% |
Engineering | 10 | 2% |
Immunology and Microbiology | 10 | 2% |
Other | 32 | 7% |
Unknown | 85 | 18% |