Interferon regulatory factor 1 (IRF1) controls the metabolic programmes of low-grade pancreatic cancer cells

Abstract

ObjectivePancreatic 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.DesignWe 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.ResultsHigh-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.ConclusionIRF1 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.

An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer

“…The Panc1005 cell line showed highest m5C-score, followed by CAPAN1, while PANC1 showed the lowest m5C-score (Figure 7H and Supplementary Table S8-7). In addition, the sequencing data from four pancreatic cancer cell lines (CAPAN1, PANC1, MIAPACA2 and CFPAC1) was acquired from GSE165949 (Alfarano et al, 2022). CAPAN1 showed the highest m5C-score, the PANC1 showed the lowest m5C-score, while MIAPACA2 cells had an almost negative m5C-score, confirming the results above (Figure 7G; Supplementary Table S8-8).…”

“…Patients without survival data were removed from further survival-related analyses. The cell line RNA-seq data were obtained from the Moffitt's cohort data (GSE71729) and GSE165949 (Alfarano et al, 2022), the latter as data normalized by "summarizeOverlaps" from the R package GenomicRanges (v. 1.38). Basic information of these datasets is listed in Supplementary Table S1, and the study workflow is presented in Supplementary Figure S1.…”

Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

“…2B ). Instead, MiaPaca2 cells contain a large deletion of the INK4/ARF locus that extends to the type I IFN gene cluster ( 45 ). However, in these cells, the type III IFN gene IFNL3 was induced in response to trametinib ( Fig.…”

“…To determine the role of ELF3 induction by trametinib in the transcriptional activation of retroelements and in the activation of the IFN response, we used ELF3-null CFPAC1 cells previously generated by genome editing in our laboratory ( 45 , 53 ). The lack of ELF3 globally and strongly attenuated induction of IFN-stimulated genes in response to trametinib ( Fig.…”

A shifting adversary: control of pancreatic cancer transcriptomic subtypes

“…KLF5 was the most highly expressed TF in low-grade versus high-grade tumors, and despite its motif not showing enrichment in low-grade enhancers, the authors demonstrated that KLF5 is an important determinant of epithelial differentiation in low-grade tumor cell lines [53] . Unlike other TFs linked with the classical subtype, KLF5 knockout in mouse models completely abolished tumorigenesis, apparently by preventing acinar-to-ductal metaplasia, an essential first step in tumorigenesis initiated in acinar cells [10,55] .…”