Complex interplay of genes underlies invasiveness in fibrosarcoma progression model

Abstract

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 pro-files, 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 accen-tuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the auto-crine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deci-phering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.