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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 01, 2024 |
| Title |
Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2 (SLAM-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
The hallmark oncogene MYC drives the progression of most human tumors, but direct inhibition of MYC by small molecules has not yet entered the clinical testing phase. As a transcription factor, MYC is dependent on a variety of binding partners for its molecular oncogenic function. Here, we explored the possibility of targeting MYC via its interactome, through a genetic screen in pancreatic ductal adenoma carcinoma (PDAC) models. While several MYC-binding partners are important for cultured PDAC cells but dispensable for tumors in their natural environment in mice, the nuclear AAA-ATPases RUVBL1 and -2 are most essential among all MYC-binding partners in vivo. Induced degradation of RUVBL by the auxin-degron system leads to rapid arrest of PDAC cells in culture and complete regression of tumors in mice, which is preceded by immune cell infiltration. Mechanistically, RUVBL is required for MYC-mediated elongation of RNA polymerase II (RNAPII) and thus for the establishment of MYC dependent oncogenic gene expression patterns. Overall, three relevant observations emerged from our study. First, our study shows that tumor cell dependencies are strongly influenced by their environment and that genetic screens in cultured cells need to be carefully validated in vivo. Second, we have shown that the auxin-degron system can be applied in a PDAC model, allowing target validation and molecular analysis in living mice. Third, our study identifies RUVBL1 as a druggable vulnerability in MYC driven cancer.
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| Overall design |
KPC-AID-Ruvbl1 cells were treated with 1 µM 5-Ph-IAA or DMSO (depletion of AID-Ruvbl1) for 3 h or 15 h (3 replicates) followed by 2 h labelling with 800 µM 4sU. One additional sample per condition was not labelled with 4sU; KPC-AID-Ruvbl1 cells were treated with 1 µM MZ-1 or DMSO (depletion of BRD4) for 5 h (3 replicates) followed by 2 h labelling with 800 µM 4sU. One additional sample per condition was not labelled with 4sU; KPC-MYC-ER cells were treated with 1 µM CB-6644 (inhibition of RUVBL1/2) or DMSO for 20 h followed by 4-hydroxytamoxifen (activation of MYC-ER) or ethanol by 4 h (3 replicates) followed by 2 h labelling with 400 µM 4sU. One additional sample per condition was not labelled with 4sU.
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| Contributor(s) |
Vogt M, Dudvarski Stankovic N, Cruz Garcia Y, Hofstetter J, Schneider K, Kuybu F, Hauck T, Adhikari B, Rocca Y, Grysczyk L, Martin B, Gebhardt-Wolf A, Wiegering A, Diefenbacher ME, Eilers M, Gasteiger G, Rosenfeldt M, Erhard F, Vos SM, Wolf E |
| Citation(s) |
38821858 |
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| Submission date |
Oct 19, 2022 |
| Last update date |
Sep 23, 2024 |
| Contact name |
Elmar Wolf |
| E-mail(s) |
[email protected]
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| Organization name |
Biocenter of the University of Würzburg
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| Department |
Department of Molecular Biology and Biochemistry
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| Lab |
Cancer Systems Biology Lab
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| Street address |
Am Hubland
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| City |
Würzburg |
| State/province |
Bavaria |
| ZIP/Postal code |
97074 |
| Country |
Germany |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL30172 |
NextSeq 2000 (Mus musculus) |
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| Samples (27)
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| This SubSeries is part of SuperSeries: |
| GSE216095 |
Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2 |
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| Relations |
| BioProject |
PRJNA892079 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE216092_SLAMseq_AID_Ruvbl1_DGE.tsv.gz |
579.6 Kb |
(ftp)(http) |
TSV |
| GSE216092_SLAMseq_CB6644_MYC_ER_DGE.csv.gz |
1.2 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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