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Published on: June 8, 2018
Engineering a drug-inducible pyroptosis platform enables precise tumor suppression in colorectal cancer
Xiang Yao1, Yu Wei2, Yuan Gao1
1Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Colorectal cancer remains a leading cause of cancer-related mortality, with long-term survival rates hindered by chemoresistance and an immunosuppressive tumor microenvironment. Gene-based therapies offer high specificity but are limited by challenges such as off-target effects, inefficient delivery, and systemic toxicity. Here, we report the design and functional validation of a chemically inducible gene circuit that harnesses Gasdermin E (GSDME) to trigger pyroptotic cell death on demand. We substituted its native proteolytic activation motif with a customized protease recognition sequence. By engineering inducible protease variants whose activity is tightly regulated by an orally bioavailable, clinically approved small molecule, we achieved precise temporal control of pyroptosis. In patient-derived organoid models, administration of the inducer led to rapid GSDME cleavage, pore formation, and robust cell lysis. In a xenograft model, oral treatment with the approved drug led to marked tumor growth inhibition. This strategy utilizes the safety and pharmacokinetics of an approved drug to enable programmable cell death, providing a versatile platform for the targeted elimination of treatment-resistant tumors.
Insights
Scientists engineered a controllable gene circuit using Gasdermin E (GSDME) to induce cancer cell death. This approach precisely triggers pyroptosis on demand, offering a new strategy for treating chemoresistant colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Colorectal cancer is a major cause of mortality, often exacerbated by chemoresistance and a suppressive tumor microenvironment.
- Current gene therapies face limitations including off-target effects, poor delivery, and systemic toxicity.
Purpose of the Study:
- To design and validate a chemically inducible gene circuit for targeted pyroptotic cell death.
- To engineer Gasdermin E (GSDME) for controlled activation via a small molecule inducer.
Main Methods:
- Engineered a gene circuit by modifying the GSDME activation motif with a protease recognition sequence.
- Developed inducible protease variants regulated by an orally bioavailable small molecule.
- Validated the system in patient-derived colorectal cancer organoids and a xenograft mouse model.
Main Results:
- Achieved precise temporal control over pyroptosis induction.
- Demonstrated rapid GSDME cleavage, pore formation, and cell lysis in organoid models upon inducer administration.
- Observed significant tumor growth inhibition in a xenograft model following oral treatment with the small molecule inducer.
Conclusions:
- The developed chemically inducible gene circuit enables programmable cell death.
- This strategy leverages the safety profile of an approved drug for targeted elimination of treatment-resistant tumors.
- Presents a versatile platform for developing novel cancer therapies.
