Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy

Carlo Pergola,Oliver Werz,Silke Rummler,Stephan Hüttel,Rolf Müller,Olga Scherer,Katrin Schubert,Alexander Mosig,Felix Nikels,Simona Pace,Angelika M Vollmar,Christina Weinigel,Andreas Koeberle,Jana Ziereisen,Martin Raasch,Stefan Zahler

doi:10.1038/srep41434

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.

Highlights

Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets
Dual targeting of Tumour-associated macrophages (TAM) and cancer cells is a promising therapeutic approach for solid tumours that are infiltrated by macrophages[19,20,21]
Pictures are representative of three independent experiments. (C) MTT and (D) Lactate dehydrogenase release (LDH) assay of M0, M1 and M2 after incubation with chondramide A as tool (ChA) for 48 h (MTT) or 24 h (LDH)

Summary

Introduction

Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. 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. Migration, differentiation and polarization to establish tumour-promoting activities of macrophages, we here hypothesized that a chemotherapeutic approach targeting actin may simultaneously affect cancer cell and macrophage biology To test this hypothesis, we utilized chondramide A as tool We demonstrate that ChA i) blocks monocyte chemotaxis, ii) kills M2, iii) activates nuclear factor kappa (NFκ)B and stress-activated protein kinases (SAPK)/c-Jun N-terminal kinase (JNK) in M1, but not in M2, connected with TNFαsecretion, and iv) increases M1-mediated cytotoxicity for cancer cells in a TNFα-dependent fashion These unique properties of ChA might be connected to direct binding to G-actin and induction of G-actin nucleation

Methods

Results

Conclusion