Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection.

BACKGROUND: Cytotoxic neural stem cells (NSCs) have emerged as a promising treatment for Medulloblastoma (MB), the most common malignant primary pediatric brain tumor. The lack of accurate pre-clinical models incorporating surgical resection and tumor recurrence limits advancement in post-surgical MB treatments. Using cell lines from two of the 5 distinct MB molecular sub-groups, in this study, we developed an image-guided mouse model of MB surgical resection and investigate intra-cavity NSC therapy for post-operative MB. METHODS: Using D283 and Daoy human MB cells engineered to express multi-modality optical reporters, we created the first image-guided resection model of orthotopic MB. Brain-derived NSCs and novel induced NSCs (iNSCs) generated from pediatric skin were engineered to express the pro-drug/enzyme therapy thymidine kinase/ganciclovir, seeded into the post-operative cavity, and used to investigate intra-cavity therapy for post-surgical MB. RESULTS: We found that surgery reduced MB volumes by 92%, and the rate of post-operative MB regrowth increased 3-fold compared to pre-resection growth. Real-time imaging showed NSCs rapidly homed to MB, migrating 1.6-fold faster and 2-fold farther in the presence of tumors, and co-localized with MB present in the contra-lateral hemisphere. Seeding of cytotoxic NSCs into the post-operative surgical cavity decreased MB volumes 15-fold and extended median survival 133%. As an initial step towards novel autologous therapy in human MB patients, we found skin-derived iNSCs homed to MB cells, while intra-cavity iNSC therapy suppressed post-surgical tumor growth and prolonged survival of MB-bearing mice by 123%. CONCLUSIONS: We report a novel image-guided model of MB resection/recurrence and provide new evidence of cytotoxic NSCs/iNSCs delivered into the surgical cavity effectively target residual MB foci.

Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model.

BACKGROUND: Surgical resection is a universal component of glioma therapy. Little is known about the postoperative microenvironment due to limited preclinical models. Thus, we sought to develop a glioma resection and recurrence model in syngeneic immune-competent mice to understand how surgical resection influences tumor biology and the local microenvironment. METHODS: We genetically engineered cells from a murine glioma mouse model to express fluorescent and bioluminescent reporters. Established allografts were resected using image-guided microsurgery. Postoperative tumor recurrence was monitored by serial imaging, and the peritumoral microenvironment was characterized by histopathology and immunohistochemistry. Coculture techniques were used to explore how astrocyte injury influences tumor aggressiveness in vitro. Transcriptome and secretome alterations in injured astrocytes was examined by RNA-seq and Luminex. RESULTS: We found that image-guided resection achieved >90% reduction in tumor volume but failed to prevent both local and distant tumor recurrence. Immunostaining for glial fibrillary acidic protein and nestin showed that resection-induced injury led to temporal and spatial alterations in reactive astrocytes within the peritumoral microenvironment. In vitro, we found that astrocyte injury induced transcriptome and secretome alterations and promoted tumor proliferation, as well as migration. CONCLUSIONS: This study demonstrates a unique syngeneic model of glioma resection and recurrence in immune-competent mice. Furthermore, this model provided insights into the pattern of postsurgical tumor recurrence and changes in the peritumoral microenvironment, as well as the impact of injured astrocytes on glioma growth and invasion. A better understanding of the postsurgical tumor microenvironment will allow development of targeted anticancer agents that improve surgery-mediated effects on tumor biology.