Abstract 965: The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis

Abstract

Despite the use of chemotherapy and surgery, the development of metastasis remains to be the leading cause of death in patients with osteosarcoma. LOX encodes for lysyl oxidase, which is an enigmatic molecule in cancer by acting as a tumor suppressor in certain tumors, but a metastatic promoter in other tumors. To investigate the function of LOX, we generated LOX overexpression mutants in two osteosarcoma cell lines and showed that higher LOX expression promoted tumor cell proliferation and invasiveness. Using an orthotopic xenograft mouse model, we further showed that osteosarcoma cells with higher LOX expression produced a higher number of mice with pulmonary metastases than the parental cell line (n=9). To characterize the mechanism of LOX-mediated metastasis, we examined the protein expression of a panel of potential downstream targets. The results demonstrated that phospho-FAK (focal adhesion kinase) expression was increased in the LOX-overexpression mutant relative to the parental cell line. Using a small molecule inhibitor of FAK, we showed that it significantly reduced the LOX-mediated metastasis in the orthotopic xenograft model. To demonstrate the clinical significance of our findings, we analyzed the expression profiling and RNAseq datasets recently generated from the TARGET osteosarcoma study. A Kaplan-Meier analysis showed that a higher level of LOX expression significantly correlated with a poor outcome (p Citation Format: Xiang Chen, John M. Hicks, Poonam Sarkar, Waleed M. Gaber, Tsz-Kwong MAN. The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 965.