PO-163 Identification of candidate genes underlying soft tissue sarcoma progression using a progression series of murine fibrosarcoma cell lines

Introduction Soft tissue sarcomas are known for their great variability in clinical behaviour, ranging from almost indolent lesions to rapidly metastasing tumours. Genes responsible for sarcoma progression have been poorly characterised by now. Towards this end, we established a unique single-background progression series of murine sarcoma cell lines, consisting of the slowly proliferating nonmotile and noninvasive cell line JUN-2, rapidly proliferating, motile and invasive cell line JUN-3, and the cell line JUN-2fos-3 that exhibits a unique transformation pattern, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. Material and methods This unique distribution of transformation related-traits made us possible to identify two separate groups of genes tentatively involved in sarcoma progression in a single transcriptomic analysis – on the one hand, proliferation-related genes could be identified by their differential expression in JUN-3 compared to both JUN-2 and JUN-2fos3, and, on the other hand, motility and invasiveness-related genes could be identified by their common expression pattern in JUN-2fos3 and JUN-3 cells compared to JUN-2. The high-throughput gene expression analysis has been performed using the GeneChip Mouse Genome 430 2.0 Array (ThermoFisher Scientific). Results and discussions In total, we identified 277 upregulated and 212 downregulated unique transcripts in JUN-2 and JUN-2fos3 compared to the JUN3 cells (adjustP -4 ). Simultaneously, we showed 29 upregulated and 112 downregulated unique transcripts in JUN3 and JUN2fos3 compared to JUN2 cell cultures (adjustP -4 ). The chemokine Ccl-8 was identified as a possible druggable target responsible for sarcoma motility, as it is overexpressed in both motile cell lines and its pharmacological inhibition significantly downregulated JUN-3 cell motility. Interestingly, the scrutiny of differentially expressed genes in the motile cell lines JUN-2fos3 and JUN-3 revealed a significant downregulation of genes that are put into context with stem cells in general (Abcg2 – 21x reduction) or specifically in sarcoma (Connective Tissue Growth Factor – 10x reduction). This is reminiscent of the phenomenon ‘go or grow’ independently described for brain tumours. Conclusion Our sarcoma cell lines could thus provide a valuable model to identify key genes responsible for sarcoma progression as well as to decipher a relationship between stemness and cancer invasion. Supported by the Czech Grant Agency project No 17–17636S.