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The cGAS-STING pathway is a master regulator of OCT4 expression in persistent sarcoma cells and enhances cellular
Giorgia Giordano1,2, Alessandra Merlini3,4, Federica Capozzi1
1Department of Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
Abstract:
Advanced sarcomas have a poor prognosis and limited therapeutic options. Disease recurrence is caused by persistent cells that survive drug treatments. The alkylating agent trabectedin, when combined with the poly (ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, exhibits variable antitumor effects in advanced sarcomas. In this study, we demonstrate that the expression of the transcription factor OCT4 is upregulated in persistent cells that survive treatment with trabectedin and olaparib, through the cGAS-STING-IRF3-IFNβ pathway. This route also leads to the upregulation of natural killer (NK) and cytokine-induced killer (CIK) lymphocyte activating ligands. These molecular events enhance the antitumor efficacy of immunotherapy with NK and CIK cells, targeting both the bulk population and residual drug-tolerant cells. In conclusion, the activation of the cGAS-STING pathway has a double-edged effect, enriching the OCT4+ persistent cell population while increasing the expression of NK/CIK ligands. The addition of olaparib to trabectedin potentiates the cGAS-STING pathway activation and the upregulation of NKG2DLs, while simultaneously counteracting the OCT4 overexpression. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy represents a promising strategy against advanced sarcomas and warrants further investigation.
Insights
Persistent cells in advanced sarcomas upregulate OCT4 via the cGAS-STING pathway, impacting treatment. Combining trabectedin and olaparib enhances immunotherapy with natural killer (NK) and cytokine-induced killer (CIK) cells.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Advanced sarcomas present poor prognoses and limited treatment avenues, with disease recurrence often stemming from drug-resistant persistent cells.
- Trabectedin, an alkylating agent, combined with the PARP1 inhibitor olaparib, shows variable antitumor effects in advanced sarcomas.
- Identifying mechanisms of drug resistance and potential therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of the transcription factor OCT4 in persistent cells surviving trabectedin and olaparib treatment in advanced sarcomas.
- To elucidate the involvement of the cGAS-STING-IRF3-IFNβ pathway in drug resistance and immune ligand upregulation.
- To evaluate the potential of combining chemotherapy with immunotherapy for enhanced sarcoma treatment.
Main Methods:
- Analysis of OCT4 expression in persistent sarcoma cells post-treatment with trabectedin and olaparib.
- Investigation of the cGAS-STING-IRF3-IFNβ pathway activation and its downstream effects.
- Assessment of the impact of combined treatments on natural killer (NK) and cytokine-induced killer (CIK) cell activating ligands.
- Evaluation of the efficacy of sequential trabectedin, olaparib, and NK/CIK cell immunotherapy in preclinical models.
Main Results:
- OCT4 expression is upregulated in persistent cells surviving trabectedin and olaparib treatment, mediated by the cGAS-STING-IRF3-IFNβ pathway.
- This pathway also upregulates natural killer (NK) and cytokine-induced killer (CIK) lymphocyte activating ligands.
- The combination of olaparib with trabectedin potentiates cGAS-STING pathway activation and NKG2DLs upregulation.
- Olaparib addition counteracts OCT4 overexpression, while enhancing NK/CIK ligand expression.
Conclusions:
- Activation of the cGAS-STING pathway in advanced sarcomas has a dual effect: enriching OCT4+ persistent cells and increasing NK/CIK ligands.
- Sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy shows promise against advanced sarcomas.
- This combined strategy targets both bulk tumor cells and residual drug-tolerant populations, warranting further clinical investigation.
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