Journal article

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

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

CELL | CELL PRESS | Published : 2014

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, ..

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University of Melbourne Researchers

Grants

Awarded by National Cancer Institute


Awarded by Cancer Research UK


Awarded by NATIONAL CANCER INSTITUTE


Funding Acknowledgements

We thank K. Funa for sharing plasmids, A. Lujambio, M. Taylor, J. Ahn, and other members of the Lowe laboratory for critical discussions and/or technical help, APGI for providing clinical data, and J.P. Morton for providing cell lines. We thank C.J. Sherr and L. Dow for their advice on experimental design and for editing the manuscript. S.W. is the recipient of the Annette Kade Fellowship from the Watson School of Biological Sciences. E.M. is supported by The Jane Coffin Childs Memorial Fund for Medical Research. S.W.L. is the Geoffrey Beene Chair of Cancer Biology and a Howard Hughes Medical Institute investigator. This work was supported by a grant from the National Cancer Institute (CA 013106).