Abstract B046: Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state

Abstract

Abstract Cancer cells undergo plasticity against stress for the survival of the fittest. Pancreatic ductal adenocarcinoma (PDAC) also shows intratumoral transcriptional heterogeneity with cell plasticity, which correlates with phenotypical aggressiveness and therapeutic resistance. Cell fates are determined by master transcription factors (TFs, also called “pioneer factors”) and their co-factors by opening up chromatin and establishing competence for gene expression specific to each cell type during normal development. Force expression of various combinations of pioneer factors can switch cell fate into other lineages, including induced pluripotent stem cells (“iPSC”). Since pluripotent stem cells do not have the cancer hallmarks of uncontrolled cell growth and migration, hypothetically, a fully reprogrammed cancer iPSC should regain gene programs to control these hallmarks of cancer. Thus, we and others have reprogrammed cancer cells into pluripotent stem cell-like cells by introducing pluripotent pioneer factors. However, intriguingly, despite the nature of the high plasticity of cancer, complete reprogramming of cancers to a pluripotent state is impeded in most cases, enabling us to study and model cancer progression. Our further studies confirm that, upon reprogramming, most PDAC cells lose the original PDAC phenotypes to some extent but remain in plasticity states during reprogramming. Herein, we further update on our efforts to optimize the reprogramming of normal pancreatic ductal epithelial cell line (PDEC) and PDAC derived from patients through the Sendai virus, which can most robustly transfer genes regardless of cell types. While control cells (e.g., acinar cells and fibroblast) were fully reprogrammed into iPSC cells, both PDEC and PDAC were impeded from being fully reprogrammed into pluripotency. Intriguingly, a subset of normal PDEC cells as well as some PDAC cell acquired a “partial reprogramming marker” upon reprogramming, suggesting that PDEC cells are stalled in early developmental states. Therefore, we now conclude that normal and cancerous pancreatic ductal cell states have an intrinsic mechanism that blocks complete reprogramming into a pluripotent state, and the oncogenic pathway is poised for activation, despite the nature of the high plasticity of PDAC. Identifying the factors responsible for maintaining this impenetrable cancer chromatin landscape is ideal for nominating therapeutic targets for intercepting PDAC plasticity. This work is supported by OHSU/CEDAR project award 68182-939-000. Citation Format: Dmytro Grygoryev, Taelor Ekstrom, Jason M. Link, Rosalie C. Sears, Jungsun Kim. Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B046.