An integrated epigenome and transcriptome analysis identifies PAX2 as a master regulator of drug resistance in high grade pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

“…Upregulation of many fibrillar collagens, including COL1A2, is a response to gemcitabine treatment in PDAC cancer cells (by analyzing data in ref. 53 ). High-dose ascorbic acid (ASC) treatment combined with gemcitabine/ Abraxane is under a phase II trial (NCT02905578), due to preclinical studies in which high-dose ASC induced cytotoxicity and oxidative stress selectively on PDAC cells but not normal cells 27 .…”

Assessment of spatial transcriptomics for oncology discovery

“…The signatures included in the Portal are summarized in Table S1 . 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 The Extended View of the Portal adds spatial views of de novo clustering and pathology compartments (described above), as well as the H&E tissue image. For gene signatures, the Extended View of the Portal also provides a dot-plot of individual gene expression values summarized by de novo clusters.…”

“…To facilitate the exploration of spatial genomics data, we developed a visualization application called the BMS Spatial Portal and released our data ( http://periscopeapps.org:3838/spatial_portal/ ). This application enables the visualization of gene-expression signatures 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ( Table S1 ) and biomarkers described in this work across all three cohorts.…”

Stem/progenitor cells in normal physiology and disease of the pancreas

“…Studies involving the embryonic pancreas as well as iPSC and ESC-derived endocrine cells have provided clues to the transcriptomic processes underpinning pancreatic development ( Krentz et al, 2018 ; Sharon et al, 2019a ; Veres et al, 2019 ). Furthermore, studies using patient derived samples have enabled analyses of transcriptomic changes in the context of metabolic disease and cancer; providing potential therapeutic targets for the respective diseases ( Aier et al, 2019 ; Peng et al, 2019 ) ( Fig. 4 ).…”