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Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model

M. Kripnerová, HS. Parmar, J. Šána, A. Kopková, L. Radová, S. Sopper, K. Biernacki, J. Jedlička, M. Kohoutová, J. Kuncová, J. Peychl, E. Rudolf, M. Červinka, Z. Houdek, P. Dvořák, K. Houfková, M. Pešta, Z. Tůma, M. Dolejšová, F. Tichánek, V....

. 2021 ; 10 (11) : . [pub] 20210525

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc21017685

Grantová podpora
PROGRESS Q39 Univerzita Karlova v Praze
PROGRESS Q40/01 Univerzita Karlova v Praze
CZ.02.1.01/0.0/0.0/16_019/0000787 Ministry of Education, Youth and Science
17-17636S Grantová Agentura České Republiky
260 538/2020 Univerzita Karlova v Praze
260 539/2020 Univerzita Karlova v Praze
LM2018132 Ministry of Education, Youth and Science

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.

Citace poskytuje Crossref.org

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$a Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.
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$a Leba, Martin $u Department of Cybernetics, Faculty of Applied Sciences, University of West Bohemia in Pilsen, 301 00 Plzen, Czech Republic
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