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Updated: Feb 18, 2026
In vitro Mesothelial Clearance Assay that Models the Early Steps of Ovarian Cancer Metastasis
Published on: February 17, 2012
Induction of DISE in ovarian cancer cells in vivo
Andrea E Murmann1, Kaylin M McMahon2,3, Ashley Haluck-Kangas1
1Department of Medicine/Division of Hematology/Oncology, Feinberg School of Medicine, Chicago, IL, USA.
Abstract:
The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3'UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nanoparticles (TLP). In vitro, TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo, two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA-TLPs.
Insights
Death receptor CD95/Fas activating shRNAs/siRNAs can eliminate cancer cells via DISE (death induced by survival gene elimination). This novel mechanism, targeting survival genes, shows therapeutic potential in ovarian cancer models.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- The death receptor CD95/Fas pathway is crucial for immune-mediated cancer cell killing.
- Short hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs) targeting CD95 or CD95 ligand (CD95L) exhibit potent cytotoxicity against cancer cells.
- A novel off-target mechanism, termed DISE (death induced by survival gene elimination), has been identified where these RNAs induce cancer cell death by targeting survival gene 3'UTRs.
Purpose of the Study:
- To investigate the in vivo induction of DISE in ovarian cancer cells.
- To explore the therapeutic potential of inducing DISE using siRNA-templated lipoprotein nanoparticles (TLPs).
Main Methods:
- Introduction of lentiviral CD95L-derived shRNA (shL3) into HeyA8 ovarian cancer xenografts in mice.
- In vitro evaluation of CD95L-derived siRNA (siL3) loaded TLPs for target silencing and cancer cell killing.
- In vivo assessment of siRNA-TLPs (siL2-TLP and siL3-TLP) for their effect on tumor growth in ovarian cancer models.
Main Results:
- DISE was successfully induced in vivo in ovarian cancer cells expressing shL3, leading to cancer cell death.
- In vitro, siL3-TLPs demonstrated selective silencing of a biosensor and killed ovarian cancer cells.
- In vivo, both siL2-TLP and siL3-TLP significantly reduced tumor growth, comparable to shL3 vector treatment.
Conclusions:
- DISE is an effective mechanism for killing cancer cells, particularly transformed cells and cancer stem cells, both in vitro and in vivo.
- siRNA-TLPs represent a promising therapeutic strategy for inducing DISE and treating ovarian cancer in vivo.
