The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila.

Jean-Philippe Parvy,Philippe Bulet,Alina Kurjan,Shu Kondo,Marcos Vidal,Anna Dostalova,Bruno Lemaître,Yachuan Yu,Julia B Cordero

doi:10.7554/elife.45061

Abstract

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs' capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

Highlights

Vast amount of evidence demonstrates the key role of systemic immunity in tumour progression and patient outcome
Tumour Necrosis Factor (TNF) is an important player in these tumour/immune interactions and has pleiotropic effects on tumours, including induction of cell death (Ham et al, 2016; Parameswaran and Patial, 2010). This function is conserved in Drosophila, where the single TNF homolog Eiger (Egr), produced by tumour-associated macrophages (TAMs), has been shown to drive cell death of neoplastic tumours, generated in larval imaginal discs by the loss of apico-basal complex components such as Disc large 1, Scribble or Lethal giant larvae (Cordero et al, 2010; Parisi et al, 2014; Parvy et al, 2018)
We have previously reported that tumours from disc large 1 Drosophila mutant larvae, activate Toll pathway in the Drosophila fat body in an Egrdependent manner, and this immune activation is necessary for TNF-dependent tumour cell death (Parisi et al, 2014)

Summary

Introduction

Vast amount of evidence demonstrates the key role of systemic immunity in tumour progression and patient outcome. Analysis of tumour phenotypes revealed increased tumour volume and decreased tumour cell death in dlg;imd and dlg;relE20 animals when compared with dlg counterparts (Figure 5B–E’ and G–J’) These data demonstrate that the Imd pathway is required for defensin upregulation, impairment of tumour growth and induction of tumour cell death in dlg mutant larvae. The TNF homolog Eiger is required for PS exposure and defensin antitumoural activity Previous studies have shown that circulating macrophage-like cells in Drosophila, called haemocytes, bind to dlg mutant tumours and contribute to cell death (Parisi et al, 2014) This process is mediated by the release of Egr from haemocytes (Cordero et al, 2010; Parisi et al, 2014), which activates the JNK pathway in target cells to promote apoptosis (Igaki et al, 2009). These results show that the sensitivity to Def is not restricted to dlg mutant tumours but might rather be a general feature of neoplastic growth induced by loss of cell polarity

Discussion

Materials and methods

Findings

Funding Funder Cancer Research UK