Dataset Information

SiRNA Library Screening Identifies a Druggable Immune-Signature Driving Esophageal Adenocarcinoma Cell Growth.

ABSTRACT: Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett's esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatics platforms, genomic studies of EAC tissues, somatic variation data of EAC from The Cancer Genome Atlas data of EAC, and pathologic and functional studies to define novel EAC-associated, and targetable, immune factors.By using a druggable genome library we defined genes that sustain EAC cell growth, which included an unexpected immunologic signature. Integrating Cancer Genome Atlas data with druggable siRNA targets showed a striking concordance and an EAC-specific gene amplification event associated with 7 druggable targets co-encoded at Chr6p21.1. Over-representation of immune pathway-associated genes supporting EAC cell growth included leukemia inhibitory factor, complement component 1, q subcomponent A chain (C1QA), and triggering receptor expressed on myeloid cells 2 (TREM2), which were validated further as targets sharing downstream signaling pathways through genomic and pathologic studies. Finally, targeting the triggering receptor expressed on myeloid cells 2-, C1q-, and leukemia inhibitory factor-activated signaling pathways (TYROBP-spleen tyrosine kinase and JAK-STAT3) with spleen tyrosine kinase and Janus-activated kinase inhibitor fostamatinib R788 triggered EAC cell death, growth arrest, and reduced tumor burden in NOD scid gamma mice.These data highlight a subset of genes co-identified through siRNA targeting and genomic studies of expression and somatic variation, specifically highlighting the contribution that immune-related factors play in support of EAC development and suggesting their suitability as targets in the treatment of EAC.

SUBMITTER: Duggan SP

PROVIDER: S-EPMC6009761 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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siRNA Library Screening Identifies a Druggable Immune-Signature Driving Esophageal Adenocarcinoma Cell Growth.

Duggan Shane P SP Garry Catherine C Behan Fiona M FM Phipps Sinead S Kudo Hiromi H Kirca Murat M Zaheer Abdul A McGarrigle Sarah S Reynolds John V JV Goldin Robert R Kalloger Steve E SE Schaeffer David F DF Long Aideen A Strid Jessica J Kelleher Dermot D

Cellular and molecular gastroenterology and hepatology 20180131 4

<h4>Background & aims</h4>Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett's esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.<h4>Methods</h4>This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatic ...[more]

PMID: 29930979

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Project description:BackgroundA key barrier to controlling esophageal adenocarcinoma (EAC) is identifying those most likely to benefit from screening and surveillance. We aimed to develop an online educational tool, termed IC-RISC™, for providers and patients to estimate more precisely their absolute risk of developing EAC, interpret this estimate in the context of risk of dying from other causes, and aid in decision-making.ResultsU.S. incidence and mortality data and published relative risk estimates from observational studies and clinical trials were used to calculate absolute risk of EAC over 10 years adjusting for competing risks. These input parameters varied depending on presence of the key precursor, Barrett's esophagus. The open source application works across common devices to gather risk factor data and graphically illustrate estimated risk on a single page. Changes to input data are immediately reflected in the colored graphs. We used the calculator to compare the risk distribution between EAC cases and controls from six population-based studies to gain insight into the discrimination metrics of current practice guidelines for screening, observing that current guidelines sacrifice a significant amount of specificity to identify 78-86% of eventual cases in the US population.ConclusionsThis educational tool provides a simple and rapid means to graphically communicate risk of EAC in the context of other health risks, facilitates "what-if" scenarios regarding potential preventative actions, and can inform discussions regarding screening, surveillance and treatment options. Its generic architecture lends itself to being easily extended to other cancers with distinct pathways and/or intermediate stages, such as hepatocellular cancer. IC-RISC™ extends current qualitative clinical practice guidelines into a quantitative assessment, which brings the possibility of preventative actions being offered to persons not currently targeted for screening and, conversely, reducing unnecessary procedures in those at low risk. Prospective validation and application to existing well-characterized cohort studies are needed.

Dataset Information

SiRNA Library Screening Identifies a Druggable Immune-Signature Driving Esophageal Adenocarcinoma Cell Growth.

Publications

siRNA Library Screening Identifies a Druggable Immune-Signature Driving Esophageal Adenocarcinoma Cell Growth.

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