Role of yes-associated protein 1 (YAP1) in human pancreatic ductal adenocarcinoma initiation and progression

Introduction: Understanding the molecular mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) initiation and progression is an urgent need to achieve more effective diagnosis and treatment to this deadly cancer. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to study PDAC initiation and progression using normal human pancreatic cells. Methods: Normal human acinar cells or cells undergoing acinar-to-ductal metaplasia (ADM, AD cells) are isolated by fluorescence-activated cell sorting (FACS), and cultured in 3D-culture system. Lentivirus carrying either YAP1-mCherry are transduced into acinar cells to study whether YAP1 is sufficient to induce ADM or is required during TGFβ-induced ADM. Lentivirus carrying either shYAP1-mCherry or shYAP1-Kras G12D -mCherry are transduced into AD cells to study whether YAP1 is required for AD cell proliferation and Kras-induced prolonged proliferation. ChIP-PCR and genome-wide ChIP-seq will be used to identify the mechanism through which YAP1 promotes PDAC development and progression. Lentivirus carrying inducible shYAP1 will be transduced into cancer producing, engineered AD cells and orthotopically transplanted into SCID mice to investigate whether inhibiting YAP1 could suppress PDAC progression. Results: We already found that TGFβ could induce ADM and oncogenic Kras could maintain the proliferation capacity of AD cells. Also, TGFβ induces YAP1 expression and TGFβ inhibitor blocks YAP1 induction during ADM process, and deleting YAP1 will suppress Kras-induced over-proliferation in AD cells, suggesting that YAP1 plays an important role in ADM, and is downstream of TGFβ as well as Kras signaling. Conclusion and significance: Successful completion of the project will give us a better understanding of how YAP1 functions in human PDAC initiation and progression. It will provide us opportunities to develop new methods for early detection and treatment of PDAC. Citation Format: Xue Yin, Jun Liu, Naoki Akanuma, Michael Nipper, Pei Wang. Role of yes-associated protein 1 (YAP1) in human pancreatic ductal adenocarcinoma initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4075.