Abstract 2418: Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma

Abstract The most recent advance in the treatment of osteosarcoma (OS) occurred in the 1980s when multi-agent chemotherapy was shown to improve overall survival compared to surgery alone. Animal model investigations can accelerate the understanding of human diseases and since few models are available for OS, we refined a rat model to ask questions regarding pathways of metastasis and metastasis biomarker predictiveness. The outbred Sprague-Dawley (SD) rat model is an immunocompetent, syngeneic model, as we implant UMR106 OS cells (ATCC), which were originally isolated from a SD OS. We developed a reproducible method to orthotopically implant cells into the tibia microenvironment and to amputate the limb for longitudinal studies. Using young rats, we also modeled pediatric OS. We found that rats develop reproducible primary and metastatic pulmonary tumors which histologically resemble human primary and metastatic osteosarcoma. Using immunohistochemistry methods, we found that primary OS is infiltrated with numerous macrophages with relatively fewer CD3+ T cells. A protein expression survey of these OS cells revealed significant expression of ErbB family receptor tyrosine kinases (ErbB2, ErbB4), which have recently been shown to be anti-inflammatory against macrophages. We also discovered that rats with osteosarcoma have markedly high serum levels of Growth Differentiation Factor 15 (GDF15), also called Macrophage Inhibitory Cytokine 1, a member of the TGF beta family of proteins, which is also frequently expressed with ErbB2 in cancers. GDF15 was measured by ELISA. Western blot analysis showed that GDF15 precursor (pro-peptide) was expressed in primary and metastases. This model will enable studies with anti-ErbB2 or GDF15 pathway inhibition to assess the role of macrophage activation in the setting of pathway inhibition and chemotherapy, as well as how pathway inhibition modulates metastasis incidence. In vivo and invitro, systems will enable the assessment of the role of GDF15 as a potential biomarker of metastasis, compared to tibial radiographic patterns, serum alkaline phosphatase, and lung histopathology. In conclusion, we have an immunocompetent, syngeneic orthotopic osteosarcoma rat model which affectively resembles human osteosarcoma, and can be used for better understanding metastasis mechanisms and metastasis biomarkers. Citation Format: Shun Ishiyama, Bailey West, Hyo-Jeong Han, Xin Guo, Tomoaki Ito, Harumi Saeki, Malcolm V. Brock, Kathleen Gabrielson. Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2418.