Objective Pancreatic ductal adenocarcinomas (PDACs) include heterogeneous mixtures of low-grade cells forming pseudoglandular structures and compact nests of high-grade cells organised in non-glandular patterns. We previously reported that low-grade PDAC cells display high expression of interferon regulatory factor 1 (IRF1), a pivotal transcription factor of the interferon (IFN) system, suggesting grade-specific, cell-intrinsic activation of IFN responses. Here, we set out to determine the molecular bases and the functional impact of the activation of IFN-regulated responses in human PDACs.
Design We first confirmed the correlation between glandular differentiation and molecular subtypes of PDAC on the one hand, and the expression of IRF1 and IFN-stimulated genes on the other. We next used unbiased omics approaches to systematically analyse basal and IFN-regulated responses in low-grade and high-grade PDAC cells, as well as the impact of IRF1 on gene expression programmes and metabolic profiles of PDAC cells.
Results High-level expression of IRF1 in low-grade PDAC cells was controlled by endodermal lineage-determining transcription factors. IRF1-regulated gene expression equipped low-grade PDAC cells with distinctive properties related to antigen presentation and processing as well as responsiveness to IFN stimulation. Notably, IRF1 also controlled the characteristic metabolic profile of low-grade PDAC cells, suppressing both mitochondrial respiration and fatty acid synthesis, which may in part explain its growth-inhibiting activity.
Conclusion IRF1 links endodermal differentiation to the expression of genes controlling antigen presentation and processing as well as to the specification of the metabolic profile characteristic of classical PDAC cells.
- pancreatic cancer
- gene expression
- energy metabolism
Data availability statement
Data are available in a public, open access repository. Datasets are available in the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE165950.
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GA, MA, PDC and CB are joint first authors.
NM and GN are joint senior authors.
NM and GN contributed equally.
GA, MA, PDC and CB contributed equally.
Correction notice This article has been corrected since it published Online First. Affiliations 4, 5 and 6 have been corrected.
Contributors GA and MA designed and carried out most of the experiments with help from MM and SP. Computational analysis: PDC and CB. Conceptualisation: GN, NM and GRD. GN and NM wrote the manuscript with contributions from all the authors. Supervision: GN, NM and GRD. Funding acquisition: GN, GRD and NM. Guarantor: GN.
Funding This study was supported by AIRC, the Italian Association for Research on Cancer (AIRC Investigator Grant 20251 to GN and AIRC 5x1000 Grant ISM) and by the Italian Ministry of Health (grant GR-2016-02361721 to GRD). This work was also partially supported by the Italian Ministry of Health with 'Ricerca Corrente' and 5x1000 funds to the IEO IRCCS. The single cell RNA-seq datasets from PDAC samples used in this research were provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. MM and GA were supported by long-term fellowships from AIRC. PDC was supported by an AIRC fellowship for Italy. GRD has been in part supported by a fellowship from the Fondazione Umberto Veronesi (FUV).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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