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dc.contributor.authorPergola, Carlo
dc.contributor.authorSchubert, Katrin
dc.contributor.authorPace, Simona
dc.contributor.authorZiereisen, Jana
dc.contributor.authorNikels, Felix
dc.contributor.authorScherer, Olga
dc.contributor.authorHüttel, Stephan
dc.contributor.authorZahler, Stefan
dc.contributor.authorVollmar, Angelika M
dc.contributor.authorWeinigel, Christina
dc.contributor.authorRummler, Silke
dc.contributor.authorMüller, Rolf
dc.contributor.authorRaasch, Martin
dc.contributor.authorMosig, Alexander
dc.contributor.authorKoeberle, Andreas
dc.contributor.authorWerz, Oliver
dc.date.accessioned2017-07-11T10:05:51Z
dc.date.available2017-07-11T10:05:51Z
dc.date.issued2017-01-30
dc.identifier.citationModulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy. 2017, 7:41434 Sci Repen
dc.identifier.issn2045-2322
dc.identifier.pmid28134280
dc.identifier.doi10.1038/srep41434
dc.identifier.urihttp://hdl.handle.net/10033/621004
dc.description.abstractTumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleModulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalScientific reportsen
refterms.dateFOA2018-06-12T23:24:02Z
html.description.abstractTumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.


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