Abstract B16: Using human patient-derived organoids to identify genetic dependencies in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable model systems to interrogate pathways involved in pancreatic tumorigenesis and to probe individual responses to novel therapies are urgently needed. To that end, we established methods to culture normal and neoplastic pancreatic duct cells as three-dimensional organoid cultures. Pancreatic organoids can be rapidly generated from resected tumors or fine needle biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Following orthotopic transplant, neoplastic organoids recapitulated the full spectrum of tumor development by forming early-grade neoplasms that progressed to locally invasive and metastatic carcinomas, demonstrating the utility of organoids to model the stages of PDA tumorigenesis. Monolayer cell lines were generated from organoid cultures with high efficiency, creating a diverse collection of new PDA cell lines. To better understand pathways involved in PDA progression, we performed transcriptomic and proteomic analyses of murine organoids derived from normal pancreatic ducts, pancreatic intraepithelial neoplasias (PanINs), and PDAs. These datasets revealed expression changes associated with early and late pancreatic tumorigenesis. To identify genes dysregulated during pancreatic tumorigenesis whose depletion impaired human PDA cells, a CRISPR-Cas competition assay was employed. Taken together, pancreatic organoids offer a novel model system for studying pancreatic cancer biology and can be used to screen for genetic dependencies in PDA. Citation Format: Lindsey A. Baker, Hervé Tiriac, Vincenzo Corbo, Sylvia F. Boj, Chang-il Hwang, Iok In Christine Chio, Danielle D. Engle, Myrthe Jager, Mariano Ponz-Sarvise, Mona S. Spector, Ana Gracanin, Tobiloba Oni, Kenneth H. Yu, Ruben van Boxtel, Meritxell Huch, Keith D. Rivera, John P. Wilson, Michael E. Feigin, Daniel Öhlund, Abram Handly-Santana, Christine M. Ardito-Abraham, Michael Ludwig, Ela Elyada, Brinda Alagesan, Giulia Biffi, Georgi N. Yordanov, Bethany Delcuze, Brianna Creighton, Kevin Wright, Youngkyu Park, Folkert H.M. Morsink, I. Quintus Molenaar, Inne H. Borel Rinkes, Edwin Cuppen, Yuan Hao, Ying Jin, Isaac J. Nijman, Christine Iacobuzio-Donahue, Steven D. Leach, Darryl J. Pappin, Molly Hammell, David S. Klimstra, Olca Basturk, Ralph H. Hruban, George Johan Offerhaus, Robert G.J. Vries, Hans Clevers, D