Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model
Onyinyechukwu Okolie1, Juli R Bago1, Ralf S Schmid1
1Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (O.O., J.R.B., S.D.H.); Division of Neuropathology, Department of Pathology and Laboratory Medicine, Department of Neurology, and Neuroscience Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (C.R.M.); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.S.S., D.M.I., R.E.B., C.R.M., S.D.H.); Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.D.H.).
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.
Insights
This study developed a mouse model to investigate glioma surgery's effects on the tumor microenvironment and recurrence. It found that while surgery reduces tumor size, injured astrocytes promote cancer cell growth and spread.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Surgical Oncology
Background:
- Surgical resection is standard for glioma treatment, but the postoperative tumor microenvironment remains poorly understood.
- Limited preclinical models hinder investigation into how surgery impacts glioma biology and the local cellular milieu.
- Developing a suitable model is crucial for understanding postsurgical changes and improving therapeutic strategies.
Purpose of the Study:
- To establish a syngeneic model of glioma resection and recurrence in immune-competent mice.
- To investigate the influence of surgical resection on glioma tumor biology and the peritumoral microenvironment.
- To elucidate the role of reactive astrocytes in postsurgical tumor recurrence and invasion.
Main Methods:
- Genetically engineered murine glioma cells with reporter genes for imaging.
- Utilized image-guided microsurgery for tumor resection in established allografts.
- Assessed tumor recurrence via serial imaging and characterized the microenvironment using histopathology and immunohistochemistry.
- Employed coculture techniques and molecular analyses (RNA-seq, Luminex) to study astrocyte injury effects.
Main Results:
- Image-guided resection significantly reduced tumor volume (>90%) but did not prevent local or distant recurrence.
- Resection-induced astrocyte injury caused temporal and spatial changes in reactive astrocytes within the peritumoral microenvironment.
- In vitro studies demonstrated that injured astrocytes promote glioma cell proliferation and migration through altered transcriptome and secretome profiles.
Conclusions:
- A novel syngeneic model for glioma resection and recurrence in immune-competent mice was successfully developed.
- The model provides critical insights into postsurgical tumor recurrence patterns and microenvironmental shifts, including the role of injured astrocytes.
- Understanding these postsurgical dynamics is essential for developing targeted therapies to enhance surgery's efficacy against glioma.
