Abstract A66: Runx3 drives metastatic programs in pancreas cancer

Abstract

Abstract The extreme proclivity of pancreatic ductal adenocarcinoma (PDA) for metastatic spread is the principal cause of mortality for this disease, even for patients who successfully undergo surgical resection of the primary tumor. We have engaged in a concerted effort to define the fundamental molecular and cellular drivers of PDA through the use of cognate genetically engineered mouse models that recapitulate the spectrum of human PDA. Recently, we incorporated conditional deletion of Smad4 into the KPC mouse model and noted a significant attenuation of metastatic burden in the resultant KPDC mice. Gene expression analysis identified the Runt family transcription factor Runx3 as highly expressed in metastatic KPC tumors, but minimally expressed in PDA from KPDC mice. We showed that aberrant expression of Runx3 strongly enhanced the metastatic potential of PDA through an orchestrated program that stimulated cancer cell invasion and migration and also helped generate a niche for disseminated cells to establish themselves in foreign tissues (such as the liver or lung) and form metastases. Runx3 expression additionally inhibited proliferation by upregulating expression of the cell cycle inhibitor Cdkn1a (p21), initiating a metastatic switch that favored PDA dissemination over local outgrowth. We have also identified influences of Runx3 expression on key developmental and immune-regulatory signaling pathways that are known to be aberrantly regulated in PDA. Because Runx3 has been shown to interact with Smad4 and p53, the genomic context of PDA expressing Runx3 critically modulates its function through de novo or altered protein complex formation. Defining the dichotomous, contextual roles of Runx3 as both a tumor “suppressor” and “promoter” may provide insight into the proximal cause of lethality in patients, thereby informing clinical prioritization of local versus systemic therapies for individual patients with PDA. Citation Format: Martin C. Whittle, Libing Feng, Ashley Dotson, Fiona Pakiam, Sunil R. Hingorani.{Authors}. Runx3 drives metastatic programs in pancreas cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A66.