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

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• 作者：Susann Weissmueller¹ ; ² ; ¹¹ ; Eusebio Manchado² ; ¹¹ ; Michael Saborowski² ; John P. Morris IV² ; Elvin Wagenblast¹ ; Carrie A. Davis¹ ; Sung-Hwan Moon³ ; Neil T. Pfister³ ; Darjus F. Tschaharganeh² ; Thomas Kitzing² ; Daniela Aust⁴ ; Elke K. Markert⁵ ; Jianmin Wu⁶ ; ⁷ ; Sean M. Grimmond⁸ ; ⁹ ; Christian Pilarsky⁴ ; Carol Prives³ ; Andrew V. Biankin⁶ ; ⁹ ; Scott W. Lowe¹ ; ² ; ¹⁰ ; ^{lowes@mskcc.org" class="auth_mail}
• 刊名：Cell
• 出版年：10 April, 2014
• 年：2014
• 卷：157
• 期：2
• 页码：382-394
• 全文大小：2521 K

文摘

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Summary

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聽vitro and metastasis formation in聽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.