title: Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy.
abstract: Tumour-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.
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schubert
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Ziereisen
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Nikels
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Scherer
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany.|Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology at Saarland University, Saarbrücken, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Hüttel
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, Jena, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, Jena, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Rummler
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany.|Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology at Saarland University, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry II, University Hospital Jena, Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Raasch
authors.affiliation: Institute of Biochemistry II, University Hospital Jena, Jena, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mosig
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000199:Actins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D056747:Immunomodulation; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D047630:Depsipeptides; D014409:Tumor Necrosis Factor-alpha; C097819:chondramide A; D020169:Caspases