Beschreibung:
Abstract Pancreatic ductal adenocarcinoma (PDA) is the most deadly disease in human malignancies. Using pancreatic organoid models, we have shown that enhancer reprogramming allows pancreatic cancer cells to acquire aggressive characteristics during disease progression. Recently we found that organoid cultures (mM) derived from metastatic lesions of KPC mice (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) can survive in the reduced condition, unlike the paired primary tumor-derived organoid cultures (mT). We implicate Engrailed-1 (EN1), a neurodevelopmental transcription factor (TF), in this process as a prosurvival factor. We show that EN1 is indispensable for organoid survival in the reduced condition, highly expressed in mM compared to mT organoid cultures, and associated with poor prognosis. Gain- and loss-of-function experiments further show that EN1 is responsible for the aggressiveness of pancreatic cancer cells in vitro (anchorage-independent growth, migration, and invasion) and in vivo. On the other hand, subcutaneous tumors derived from EN1 expressing mT organoids exhibit squamous-like differentiation compared to control. In line with this, squamous-type PDA patients tend to express EN1 compared to other subtypes of PDA. Furthermore, EN1 perturbation renders the changes of squamous-PDA identity and KDM6A deficiency signatures. Mechanistically, EN1 can physically interact with KDM6A and repress H3K4me3 occupancy in a subset of genes without affecting H3K27me3 and H3K27ac occupancies, suggesting that the regulation of COMPASS (Complex Proteins Associated with Set1) activity by EN1 might be critical in this process. Finally, by combining EN1 with FOXA1, previously shown to be responsible for enhancer activation in PDA organoids, we were able to fully reprogram pancreatic cancer cells into highly aggressive pancreatic cancer cells. In sum, we report that EN1 confers the aggressiveness of pancreatic cancer cells via regulation of COMPASS activity and contributes to squamous-type identity and PDA progression. Citation Format: Chang-il Hwang, Jae-Seok Roe, Eun Jung Lee, Claudia Tonelli, Tim D.D. Somervile, Melissa Yao, Joseph P. Milazzo, Hervé Tiriac, Youngkyu Park, Christopher Vakoc, David Tuveson. Engrailed-1 promotes pancreatic cancer progression via antagonizing COMPASS activity [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B25.