Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.

Biomedical Center Faculty of Medicine in Pilsen Charles University 323 00 Plzen Czech Republic

Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute 602 00 Brno Czech Republic

Department of Cybernetics Faculty of Applied Sciences University of West Bohemia in Pilsen 301 00 Plzen Czech Republic

Department of Medical and Molecular Biology Faculty of Medical Sciences in Zabrze Medical University of Silesia in Katowice 41 808 Zabrze Poland

Department of Medical Biology and Genetics Faculty of Medicine in Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Pathology University Hospital Brno 625 00 Brno Czech Republic

Institute of Biology Faculty of Medicine in Pilsen Charles University 323 00 Plzen Czech Republic

Institute of Medical Chemistry and Biochemistry Faculty of Medicine in Pilsen Charles University 301 66 Plzen Czech Republic

Institute of Pathological Physiology Faculty of Medicine in Pilsen Charles University 323 00 Plzen Czech Republic

Institute of Physiology Faculty of Medicine in Pilsen Charles University 323 00 Plzen Czech Republic

Internal Medicine 5 Medical University of Innsbruck 6020 Innsbruck Austria

Tyrolean Cancer Research Institute 6020 Innsbruck Austria

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