Abstract 368: Defining the invasive gene signature using patient derived pancreatic cancer organoids

Abstract

Abstract Pancreatic cancer mortality is rising due to late detection and established metastasis. Despite the recent advances in cancer research, metastasis research has been hampered by the lack of models that recapitulate this complex process. Traditional cell culture and animal models provided insights on cancer cell migration and dissemination. But local invasion, which precedes all the events in the metastatic cascade, remains poorly understood. Patient-derived organoids (PDO) present an innovative platform in which the earliest step of metastasis can be observed and manipulated ex vivo. We developed a pancreatic cancer organoid model using surgically resected tumors from The Johns Hopkins Hospital. We previously reported that there are two invasive patterns in pancreatic cancer PDOs - Mesenchymal and Collective invasion, with one dominating pattern in every PDO culture. Here, we describe the gene expression signature associated with local invasion in pancreatic cancer by comparing the whole transcriptome of matched invasive and non-invasive organoids from the same tumor. For this study, PDOs were cultured for 7 days ex vivo and we manually collected 50 invasive and non-invasive organoids from each culture for RNA-seq analysis. To date, the invasive and non-invasive organoids from 6 PDO lines have been analyzed. The list of differentially expressed genes between invasive and non-invasive organoids includes 1,106 genes with FDR 0.001, with DACT1, DKK3 and KIF26B being most differentially expressed. Pathway analysis identifies that the invasive phenotype is associated with extracellular matrix receptor interaction, focal adhesion and PI3K-Akt signaling pathways. In conclusion, our findings revealed a distinct gene expression signature between invasive and non-invasive cells in PDOs. Interestingly, we did not find significant up or down-regulation in the classical EMT markers in our results, which suggests possible pancreatic cancer-specific metastasis programs exist. We believe our results can inform new diagnostic and prognostic tools and help identify anti-metastasis targets in pancreatic cancer. Citation Format: Yea Ji Jeong, Michael G. Lerner, Yuchen Ge, Hildur Knutsdottir, Bernat Navarro-Serer, Peter E. Chianchiano, Andrew J. Ewald, Joel S. Bader, Laura D. Wood. Defining the invasive gene signature using patient derived pancreatic cancer organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 368.