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Generating Shigella that internalize into glioblastoma cells
Austin Shipley1, Gabriel Frampton1, Bryan W Davies2,3
1Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.
Frontiers in Oncology
|December 11, 2023
Summary
Researchers engineered Shigella flexneri bacteria to selectively target and enter glioblastoma (GBM) brain tumor cells. This novel bacterial platform offers a promising new approach for brain cancer drug delivery systems.
Area of Science:
- Microbiology
- Oncology
- Biotechnology
Background:
- Microorganisms are emerging as viable drug delivery systems for cancer, offering advantages like localized therapeutic protein production.
- Current microbial systems, such as AAV9 and herpes virus, face limitations including small payload capacity, poor cancer cell selectivity, and low inherent toxicity.
- Glioblastoma (GBM) presents a significant challenge due to its aggressive nature and limited treatment options.
Purpose of the Study:
- To develop a novel bacterial strain of *Shigella flexneri* capable of selective internalization into glioblastoma (GBM) cells.
- To establish a foundation for a new generation of bacterial-based drug delivery systems for brain tumors.
Main Methods:
- Iterative co-culture assays were employed to select for *S. flexneri* strains with enhanced GBM cell internalization.
- An in-cell western assay was developed to identify high-affinity GBM-infecting clones from patient samples without iterative co-culture.
- Mechanism of internalization was investigated, identifying a myristoylation-modified factor.
Main Results:
- A modified *S. flexneri* strain demonstrated selective internalization into GBM cells after 50 rounds of co-culture, infecting 95% of cells within 2 hours.
- The engineered Shigella exhibited a 124-fold preference for GBM cell lines over normal astrocytes.
- Internalization was confirmed to be mediated by a myristoylation-modified factor.
Conclusions:
- A novel bacterial platform using *Shigella flexneri* has been successfully engineered for preferential internalization into brain tumor cells.
- This platform presents significant advantages over existing therapeutic strategies and other microbial delivery systems for brain tumor treatment.
