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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 (Screen) |
| Organisms |
Mus musculus; synthetic construct |
| Experiment type |
Other
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| Summary |
Objective:
The hallmark oncogene MYC drives the progression of most tumorstumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC).
Design:
To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumorstumours in mice.Results:Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumorstumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumortumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immuno-evasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer.
Conclusion:
One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
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| Overall design |
Pooled shRNA Screen in cultured KPC cells, treatment with doxycycline or ethanol (3 replicates); pooled shRNA Screen in KPC allograft tumors, treatment with doxycycline or ethanol (5 replicates)
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| Web link |
https://doi.org/gutjnl-2023-331519
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| Contributor(s) |
Vogt M, Dudvarski Stankovic N, Cruz Garcia Y, Hofstetter J, Schneider K, Kuybu F, Hauck T, Adhikari B, Hamann A, Rocca Y, Grysczyk L, Martin B, Gebhardt-Wolf A, Wiegering A, Diefenbacher ME, Gasteiger G, Knapp S, Saur D, Eilers M, 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) |
elmar.wolf@biozentrum.uni-wuerzburg.de
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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) |
| GPL19424 |
Illumina NextSeq 500 (synthetic construct) |
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| Samples (20)
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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 |
PRJNA892078 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE216091_KPC_allograft_screen_TOC.csv.gz |
14.0 Kb |
(ftp)(http) |
CSV |
| GSE216091_KPC_allograft_screen_preexperiment_TOC.csv.gz |
6.3 Kb |
(ftp)(http) |
CSV |
| GSE216091_KPC_culture_screen_TOC.csv.gz |
8.9 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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