Abstract 5350: Single cell RNA-seq reveals transcriptionally distinct subpopulations within patient-derived pancreatic cancer organoids

Abstract

Advances in 3D cell culture over the last decade have enabled the establishment of organoid models from a multitude of organs in varying stages of development and disease. Organoids recapitulate the tissue-specific cell types and exhibit similar morphology and spatial organization as the organ it is derived from. However, to the best of our knowledge, tumor organoids have never been profiled at a single cell level. In this study, we applied Drop-seq, a high throughput single cell RNA-seq platform, to characterize the different cell types present in pancreatic cancer organoids. We sequenced the transcriptomes of 5494 single cells from organoids derived from a patient undergoing a Whipple procedure for pancreatic ductal adenocarcinoma (PDAC). We then developed a novel clustering approach based on a class of probabilistic generative models called topic models, leading to the identification of two subpopulations of cells. One subgroup expressed marker genes known to play important roles in PDAC biology, such as MUC1, CLDN4 and GAS5. Interestingly, this subgroup also bore markers for cancer stem cells (HES1 and SQSTM1) that have been found by multiple studies to mediate chemoresistance in PDAC. The other subpopulation differentially expressed AGR2 and TMBIM6, which are associated with endoplasmic reticulum (ER) stress and correlates with invasiveness of PDAC cell lines. Functional studies are underway to determine the exact role of these subgroups, but our preliminary findings are suggestive of a subpopulation of cells that maybe involved in resistance to chemotherapy. This is consistent with the clinical progression of this patient's cancer, suggesting that rapid, inexpensive single cell transcriptomics might provide more precise molecular information to personalized medicine programs than traditional RNA-seq alone. Citation Format: Mohana Ray, Rajib K. Nandi, Isabel Romero Calvo, Kori Kirby, Christopher Weber, Hedy L. Kindler, Mary Buschmann, Kevin Roggin, Kevin P. White. Single cell RNA-seq reveals transcriptionally distinct subpopulations within patient-derived pancreatic cancer organoids [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 5350.