Abstract PR12: IL6-mediated self-seeding functions to prevent osteosarcoma metastasis

Abstract Osteosarcoma (OS) is the most common primary bone tumor, striking primarily adolescents and young adults. OS mortality occurs primarily as a consequence of metastatic spread to the lungs, and when OS metastasizes it resides in the lung 98% of the time. Oncologists have long observed that metastases tend to appear after removal of a primary tumor. Previously, others have explained this phenomenon by invoking the production of “metastasis suppressors” by the primary tumor. Recently, we and others have described how circulating tumor cells most commonly return to the primary tumor, where the microenvironment is particularly favorable to tumor growth. This occurs by way of a process called “self-seeding.” However, if OS cells exhibit true self-seeding, this raises a distinct possibility that resection of the primary tumor could affect the behavior of circulating tumor cells. We therefore sought to answer the question: does resection of a primary OS tumor drive redirection of circulating tumor cells toward sites of metastasis (“next best” sites)? To answer this, we first sought to identify candidate mediators of tumor cell chemotaxis that drive self-seeding. We examined production of a panel of candidate mediators by ELISA of conditioned OS supernatants. Transwell migration assays using the same candidates as chemoattractants identified responses to cytokines produced by OS cells. The results show that specific cytokines produced by most OS cells reliably mediate chemoattraction. We suspected that these cytokines play a role in OS self-seeding and that removal of a primary tumor would remove this signal, terminating self-seeding and redirecting circulating tumor cells toward colonization of the lung. To test this hypothesis we moved our studies into in vivo models. First, we examined tumor cell burden in the lung after amputation of an orthotopic tumor compared to that in mice that retained their primary tumor. Results showed that amputation of the primary tumor results in increased OS tumor cell burden in the lungs. We next asked how the presence of a primary tumor impacts the migration of tail vein-injected OS cells to the lung. Comparison of lungs from mice bearing a primary tumor to those with no primary tumor showed a decreased number of OS cells recovered from the lung. These labeled tumor cells were easily recovered in the primary tumors, suggesting a shift in recruitment from the lungs to the primary tumor. Our data suggest that a loss of self-seeding in OS on excision of the primary tumor increases metastatic burden. We are now exploring ways to leverage this biology in the development of novel therapies that prevent metastatic disease. This abstract is also being presented as Poster B31. Citation Format: Amanda Saraf, Amy C. Gross, Helene LePommellet, Sophia M. Vatelle, Ryan D. Roberts. IL6-mediated self-seeding functions to prevent osteosarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR12.

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