Abstract C54: Pdgfrb is an essential mediator of p53(mut)-driven metastasis in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer due to its high metastatic potential and resistance to existing treatments. Recent advances in cancer genomics have identified mutations and copy number changes that are linked to pancreatic cancer but which of these influence metastatic behavior remain poorly understood. 50-80% of PDACs carry a mutation in the TP53 tumor suppressor gene (p53(mut)), which possibly results in a gain-of-function that contributes to, amongst others, tumor cell invasiveness. Therefore the aim of this study was to explore the underlying molecular pathways of invasive PDAC that are mediated by TP53(mut). To this end, we combined cell lines, murine models, and RNA interference to confirm that p53(mut)-expressing tumors acquire a higher invasive capability, which is dependent on the continued expression of the mutant allele. In-depth transcriptional profiling of p53(mut) versus knockdown cells identified downstream mediators responsible for the gain-of-function phenotype. Specifically, we conducted a follow-up invasion screen to analyse the top 40 deregulated genes for their potential to induce invasiveness and we identified Platelet-derived growth factor receptors isoform b (Pdgfrb) as a p53(mut) downstream mediator. Moreover, we found that the expression of Pdgfrb is transcriptionally regulated by p73. In the presence of p53(mut) proteins, a direct p73-p53(mut) interaction alleviates the inhibitory effect that p73 exerts on the Pdgfrb promoter, thereby inducing Pdgfrb expression and, hence, invasiveness. Attenuating Pdgfrb levels by RNAi or a small molecule inhibitor reduced cellular invasion in a p53(mut) background, thereby mimicking the effects of p53-null cells. We confirmed these findings in several human pancreatic cancer cells. More importantly, we found that elevated Pdgfrb expression in human colorectal and ovarian cancers predicts poor metastasis-free survival, thereby confirming our hypothesis that high Pdgfrb levels drive metastases development. Citation Format: Susann Weissmueller, Michael Saborowski, Eusebio Manchado, Vishal Thapar, Scott W. Lowe. Pdgfrb is an essential mediator of p53(mut)-driven metastasis in pancreatic cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C54.