Abstract A24: Development of a survivable thoracic neuroblastoma mouse model for the study of the extra-adrenal tumor microenvironment
Authors: Grant Christa N. , Sun Lidan , Liu Zhenqiu , Wang Hong-Gang 
Published: June 2020

Neuroblastomas arise from neural crest cells of the paraspinal ganglia and the adrenal medulla, leading to heterogeneity in tumor presentation and location. Outcomes remain poor despite intensified multimodality treatment strategies. Primary tumor site is an independent predictor of survival in all risk groups independent of MYCN amplification status. Adrenal tumors have the worst outcomes; thoracic and cervical tumors carry a more favorable prognosis. We hypothesized that factors specific to the adrenal microenvironment enhance tumor invasion and metastasis. To identify factors that account for the survival differential of neuroblastoma based on primary tumor site, we queried the publicly available national database (TARGET) of human neuroblastoma tumors. 1,076 tumors were categorized by primary tumor site. Children with thoracic tumors had a much more favorable outcome than adrenal primary tumors. Gene expression patterns were significantly different between tumor sites for the 229 patients with microarray data. In general, upregulated genes in the thorax were associated with improved survival, and those in the adrenal gland with poor survival. Enrichment clustering revealed most genes differentially expressed were related to cell-cell junctions. We developed a model system for the study of extra-adrenal neuroblastoma. Luciferin-tagged 9464D neuroblastoma cells suspended in Matrigel were injected into the subpleural space in the left posterior chest of C57/Bl6 mice after thoracotomy. In the comparison group, 9464D cells were injected into the left adrenal gland as previously described in the literature. Mice were imaged weekly using IVIS. Solid tumors developed in the thoracic cavity at the same rate and efficiency as in the adrenal as early as one week following surgery. The survival rate from the surgery is equivalent, though the physiologic tolerance for large tumors after three weeks was lower in the thorax group. The human end point due to large tumor burden was 4 weeks for thoracic implants, compared to 6 weeks for adrenal. Our model makes it possible for the first time to investigate the distinct tumor microenvironments of the adrenal gland and the posterior mediastinum. Using our innovative mouse model, future studies will investigate the role of the differentially expressed genes in tumorigenesis, particularly those related to the cytoskeleton and cell-cell adhesion. Identification of the mechanisms by which cell adhesion molecules affect neuroblastoma initiation, growth, and metastasis in different tumor locations will help explain the differences in clinical outcomes between groups and will open innovative new avenues for therapeutic targeting.

Citation Format: Christa N. Grant, Lidan Sun, Zhenqiu Liu, Hong-Gang Wang. Development of a survivable thoracic neuroblastoma mouse model for the study of the extra-adrenal tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A24.