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| Status |
Public on Feb 19, 2024 |
| Title |
Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
While pancreatic ductal adenocarcinomas (PDAC) are addicted to KRAS-activating mutations, inhibitors of downstream effectors in the KRAS pathway, such as the clinically approved MEK1/2 kinases inhibitor Trametinib, are devoid of significant therapeutic effects. Nevertheless, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway can induce novel functional states and vulnerabilities of potential therapeutic relevance. An in-depth molecular analysis of the transcriptional and epigenomic alterations occurring in PDAC cells in the initial hours after MEK1/2 inhibition by Trametinib, unveiled a massive induction of a large number of retroelements, in particular endogenous retroviruses (ERVs), that in these cells escaped epigenetic silencing. In turn, the increased abundance of ERV-derived double stranded RNAs induced a strong Interferon (IFN) response. Pathway deconvolution allowed us to track ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated non-silenced retroelements and synergized with IRF1 (Interferon regulatory factor 1) in the activation of interferons and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the design of combination therapies in immuno-oncology.
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| Overall design |
To determine the enrichment of retrotransposon sequences in differentially acetylated regions, we generated H3K27ac ChIP-seq data sets in two low-grade (CAPAN2 and CFPAC1) and two high-grade (MiaPaca2 and PANC1) PDAC cell lines that were sampled in the untreated condition (UT) and at multiple time points (3h, 12h and 24h) after Trametinib treatment.
To quantify the genomic locus-specific levels of H3K9me3 after Trametinib treatment, we generated H3K9me3 ChIP-seq data sets in CFPAC1 cells that were sampled in the untreated condition (UT) and at multiple time points (3h, 12h, 24h and 48h) after Trametinib treatment.
To assess whether ELF3 binds ERVs and other retroelements induced by Trametinib, we generated ELF3 ChIP-seq data sets in untreated and Trametinib-treated (24h) CFPAC1 cells.
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| Contributor(s) |
Cortesi A, Gandolfi F, Arco F, Valli E, Polletti S, Noberini R, Gualdrini F, Attanasio S, Citron F, Rodighiero S, Mitro N, Bonaldi T, Ghisletti SM, Viale A, Diaferia GR, Natoli G |
| Citation(s) |
38536927 |
| |
| Submission date |
Jul 25, 2023 |
| Last update date |
Apr 04, 2024 |
| Contact name |
Gioacchino Natoli |
| Organization name |
European Institute of Oncology
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| Department |
Department of Experimental Oncology
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| Street address |
Via Adamello 16
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| City |
Milan |
| ZIP/Postal code |
20139 |
| Country |
Italy |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (51)
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| GSM7660146 |
Capan2 cells, ChIPseq H3K27ac, Untreated, Rep1 |
| GSM7660147 |
Capan2 cells, ChIPseq H3K27ac, Untreated, Rep2 |
| GSM7660148 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 3h, Rep1 |
| GSM7660149 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 3h, Rep2 |
| GSM7660150 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 12h, Rep1 |
| GSM7660151 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 12h, Rep2 |
| GSM7660152 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 24h, Rep1 |
| GSM7660153 |
Capan2 cells, ChIPseq H3K27ac, Trametinib 24h, Rep2 |
| GSM7660154 |
Cfpac1 cells, ChIPseq H3K27ac, Untreated, Rep1 |
| GSM7660155 |
Cfpac1 cells, ChIPseq H3K27ac, Untreated, Rep2 |
| GSM7660156 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 3h, Rep1 |
| GSM7660157 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 3h, Rep2 |
| GSM7660158 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 12h, Rep1 |
| GSM7660159 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 12h, Rep2 |
| GSM7660160 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 24h, Rep1 |
| GSM7660161 |
Cfpac1 cells, ChIPseq H3K27ac, Trametinib 24h, Rep2 |
| GSM7660162 |
MiaPaca2 cells, ChIPseq H3K27ac, Untreated, Rep1 |
| GSM7660163 |
MiaPaca2 cells, ChIPseq H3K27ac, Untreated, Rep2 |
| GSM7660164 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 3h, Rep1 |
| GSM7660165 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 3h, Rep2 |
| GSM7660166 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 12h, Rep1 |
| GSM7660167 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 12h, Rep2 |
| GSM7660168 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 24h, Rep1 |
| GSM7660169 |
MiaPaca2 cells, ChIPseq H3K27ac, Trametinib 24h, Rep2 |
| GSM7660170 |
Panc1 cells, ChIPseq H3K27ac, Untreated, Rep1 |
| GSM7660171 |
Panc1 cells, ChIPseq H3K27ac, Untreated, Rep2 |
| GSM7660172 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 3h, Rep1 |
| GSM7660173 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 3h, Rep2 |
| GSM7660174 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 12h, Rep1 |
| GSM7660175 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 12h, Rep2 |
| GSM7660176 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 24h, Rep1 |
| GSM7660177 |
Panc1 cells, ChIPseq H3K27ac, Trametinib 24h, Rep2 |
| GSM7660178 |
Cfpac1 cells, ChIPseq H3K9me3, Untreated, Rep1 |
| GSM7660179 |
Cfpac1 cells, ChIPseq H3K9me3, Untreated, Rep2 |
| GSM7660180 |
Cfpac1 cells, ChIPseq H3K9me3, Untreated, Rep3 |
| GSM7660181 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 3h, Rep1 |
| GSM7660182 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 3h, Rep2 |
| GSM7660183 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 3h, Rep3 |
| GSM7660184 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 12h, Rep1 |
| GSM7660185 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 12h, Rep2 |
| GSM7660186 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 12h, Rep3 |
| GSM7660187 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 24h, Rep1 |
| GSM7660188 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 24h, Rep2 |
| GSM7660189 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 24h, Rep3 |
| GSM7660190 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 48h, Rep1 |
| GSM7660191 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 48h, Rep2 |
| GSM7660192 |
Cfpac1 cells, ChIPseq H3K9me3, Trametinib 48h, Rep3 |
| GSM7660193 |
Cfpac1 cells, ChIPseq ELF3, Untreated, Rep1 |
| GSM7660194 |
Cfpac1 cells, ChIPseq ELF3, Untreated, Rep2 |
| GSM7660195 |
Cfpac1 cells, ChIPseq ELF3, Trametinib 24h, Rep1 |
| GSM7660196 |
Cfpac1 cells, ChIPseq ELF3, Trametinib 24h, Rep2 |
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| This SubSeries is part of SuperSeries: |
| GSE238200 |
Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer |
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| Relations |
| BioProject |
PRJNA998353 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE238197_RAW.tar |
28.7 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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