Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

Abstract

Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.

Genomic and Epigenomic Characterization of Tumor Organoid Models

“…In addition to the DNA methylome, chromatin accessibility landscapes of tumor organoids have also been characterized. For example, a recent work performed the assay for transposase-accessible chromatin with sequencing (ATAC-Seq) on 41 PDOs from pancreatic cancer patients [ 21 ]. These PDOs were derived from various histological classifications, including PDAC, intraductal papillary mucinous neoplasms, acinar cell carcinoma, and pancreatic neuroendocrine neoplasms, allowing for the association between differential chromatin accessibility and tumor histopathology.…”

“…In-depth, multi-layered epigenetic characterizations of PDOs have enabled the establishment of drug–epigenome interactions. A high-throughput drug screening of the pancreatic cancer PDOs [ 21 ] revealed chromatin accessibility signatures associated with sensitivity to either cytotoxic chemotherapeutics or targeted inhibitors. For example, an ATAC-seq peak assigned to the NCOR2 gene was correlated with cellular sensitivity to Go6976, an inhibitor of the JAK/STAT3 pathway, congruent with the finding that NCOR2 modulates activity of the JAK/STAT3 pathway [ 37 ].…”

Progress of 3D Organoid Technology for Preclinical Investigations: Towards Human In Vitro Models

“…Together with CRISPR-Cas9, pancreatic organoids are applied to detect drug-gene interactions, whereby ARID1A mutations were found to be associated with increased sensitivity to the kinase inhibitors, like dasatinib and VE-821 [106]. Omics data on 84 pancreatic cancer organoid lines indicate the association between chromatin accessibility signatures and drug sensitivity based on analysis of 283 epigenetic-related chemicals and five chemotherapeutic drugs [108], providing deep sights into drug-tissue reactive mechanisms.…”

Review on Advanced Cancer Modeling for a Cancer Study

“…Given that the characteristics of tumor organoids derived from cancer patients faithfully recapitulate the architecture of their original tumor tissues and organoids, cancer-organoid-culture technology has expanded to other types of cancers. Many researchers have established long-term organoid cultures by using primary-colon [ 15 , 44 ], lung [ 45 , 46 , 47 ], esophageal [ 48 ], pancreatic [ 49 , 50 , 51 ], prostate [ 51 , 52 , 53 ], breast [ 30 , 54 , 55 ], stomach [ 56 , 57 ], liver [ 40 , 58 ], and endometrial [ 59 , 60 ] cancer and normal tissues.…”