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Published on: March 10, 2015
Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer
Ewelina Szymańska1, Paulina Nowak1, Krzysztof Kolmus1
1Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
Abstract:
Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT-dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti-tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B-deficient cancers.
Insights
Researchers found that deleting the VPS4B gene, common in colorectal cancer (CRC), creates a vulnerability. Its paralog, VPS4A, becomes a synthetic lethal partner, offering new druggable targets for precision cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Somatic copy number alterations are key drivers of cancer.
- Loss of tumor suppressor genes can lead to passenger gene deletions, presenting therapeutic opportunities.
- VPS4B, involved in membrane remodeling, is frequently deleted in cancers like colorectal cancer (CRC).
Purpose of the Study:
- To identify therapeutic strategies targeting passenger genes like VPS4B in cancer.
- To investigate the functional interaction between VPS4B and its paralog VPS4A.
- To explore the potential of targeting VPS4B-deficient cancers through synthetic lethality.
Main Methods:
- Analysis of VPS4B mRNA and protein levels in CRC patient samples.
- In vitro and mouse xenograft studies to identify synthetic lethal interactors of VPS4B.
- Transcriptome analysis and assessment of cell death and immune responses upon VPS4B and VPS4A depletion.
Main Results:
- VPS4B is downregulated in colorectal cancer (CRC) patient samples.
- VPS4A was identified as a synthetic lethal partner of VPS4B.
- Simultaneous depletion of VPS4B and VPS4A induced cell death and released immunomodulatory molecules.
Conclusions:
- VPS4B is a passenger gene frequently deleted in cancer, particularly CRC.
- VPS4A acts as a synthetic lethal interactor for VPS4B.
- Targeting VPS4A offers a potential precision therapy for VPS4B-deficient cancers, with implications for immunotherapy.
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