Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

A combined genomic approach unveils the transcriptional basis of heterogeneity of human pancreatic ductal adenocarcinoma.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Chiara Balestrieri

PROVIDER: E-GEOD-64560 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer.

Diaferia Giuseppe R GR Balestrieri Chiara C Prosperini Elena E Nicoli Paola P Spaggiari Paola P Zerbi Alessandro A Natoli Gioacchino G

The EMBO journal 20160114 6

The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, ...[more]

PMID: 26769127

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Project description:Gene regulatory networks that govern hematopoietic stem cells (HSC) and leukemia–initiating cells (L-IC) are deeply entangled. Thus, the discovery of compounds that target L-IC while sparing HSC is an attractive but difficult endeavor. Presently, most drug discovery approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPC) to assess therapeutic index. Here, we present a combined in vitro and in vivo strategy to identify compounds specific to L-IC in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which most were toxic to normal HSPC. Of the 10 compounds that passed this initial filter, we chose to characterize a single compound, kinetic riboside (KR), on AML L-IC and HSPC. KR demonstrated comparable efficacy to standard therapies against 63 primary AMLs. In vitro, KR effectively targeted the L-IC-enriched CD34+CD38- AML fraction, while sparing normal HSPC enriched fractions, although these effects were mitigated on HSC assayed in vivo, and highlights the importance of in vivo L-IC and HSC assays to measure function. Overall, we provide a novel approach to screen large drug libraries for the discovery of anti-L-IC compounds for human leukemias. The gene expression profile of TEX and M9-ENL1 cells were compared to HL-60 (Series GSE16160, GSE28185) and THP1 (Series GSE28185), to determine if TEX and M9-ENL1 cells were more enriched in stem cell (embryonic, adult, leukemia, and cancer) gene sets using Gene Set Enrichment Analysis (GSEA). TEX and M9-ENL1 cells were treated with DMSO in triplicate. Total RNA was harvested and analyzed with the Affymetrix Human Genome U133A 2.0 Array. Raw data was background corrected with RMA, normalized using quantiles method, corrected using only PM values, and median polished to generate log2 values. Published HL-60 and THP-1 raw data using the same Affymetrix array were processed identically. To account for batch variation, the log2 values were adjusted using ComBat in GenePattern with a parametric Empirical Bayes priors distribution estimation method and without covariate analysis.

Dataset Information

A combined genomic approach unveils the transcriptional basis of heterogeneity of human pancreatic ductal adenocarcinoma.

Publications

Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer.

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