TMOD-12: A novel patient-derived xenograft model of brain metastasis


Aurora Neuroscience Innovation Institute


INTRODUCTION: The establishment of a disease model that adequately reflects the characteristics of metastatic brain tumors is crucial to the development of novel therapeutics. Patient-derived xenograft (PDX) models have a high clinical relevance, offering the potential for individualized patient treatment. Previous research demonstrated that successful PDX modeling can be achieved by direct intracranial implantation of metastatic cells or tissue into the lateral ventricle and frontal cortex, or through the use of a subarachnoid catheter placed into the cisterna magna. However, it is not known if one method is superior. Since injection of metastatic cells into the cerebrospinal fluid (CSF) increases the probability of cancer cell dissemination, we hypothesized that CSF injection of metastatic cells would yield a higher success rate of tumor development compared to animals that were injected in the frontal cortex.

METHODS: Patient-derived brain metastases obtained at surgery were immediately processed into single cell suspension and adaptively cultured as spheres in progenitor cell-enriching condition. After passage 2-6, 5 X 104 – 1 X 105 cells were injected into the frontal cortex, lateral ventricle, or cerebral aqueduct of female athymic nude mice at 6 – 10 weeks of age. The brains of neurologically symptomatic mice were histologically examined using 5-micron paraffin sections.

RESULTS: We found that mice injected at the cerebral aqueduct displayed higher rate of tumorigenicity and shorter time to tumor development than those injected at the frontal cortex or lateral ventricle. (Figure 1)

CONCLUSION: To the best of our knowledge this is the first report in which the cerebral aqueduct has been targeted for metastatic PDX modeling. Our data indicate that intracranial injection of metastatic cells into the cerebral aqueduct is a reproducible model to study both local growth of metastases and leptomeningeal disease.

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